Effects of a short course of oral phosphate treatment on serum parathyroid hormone (1–84) and biochemical markers of bone turnover: A dose-response study

Summary To investigate the possible use of oral phosphate as an activator of bone remodeling in coherence treatment of osteoporosis, 82 postmenopausal females, aged 50–75 years, were randomized to treatment with oral phosphate (750, 1500, or 2550 mg/day) or placebo for 7 days and followed for 4 months thereafter. All patients had sustained at least one previous fracture of the distal forearm and had a bone mineral content of the contralateral forearm or bone mineral density of the lumbar spine lower than normal mean for age. Urinary phosphate/creatinine ratio increased in a dose-dependent fashion during treatment (P<0.001), whereas no significant changes were seen in serum phosphate or serum calcium. Serum parathyroid hormone (PTH) rose significantly (P<0.05) during treatment to a maximum of 36 and 33% in the groups receiving 1500 and 2250 mg/day, respectively, whereas serum 1,25-dihydroxycholecalciferol remained unchanged. In the group receiving 1500 mg/day, mean serum osteocalcin was increased in the period from day 1 to day 28 (P<0.05), but no significant changes were observed in urinary hydroxyproline/creatinine ratio, or serum bone alkaline phosphatase. We conclude that a short course of oral phosphate treatment increases serum PTH considerably. Furthermore, 1500 mg/day but not 2250 mg/day increases serum osteocalcin. No clear biochemical evidence, however, of increased activation of bone remodeling could be demonstrated in either group.     

Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism.

In a large proportion of the patients with primary hyperparathyroidism (PHPT), a variable degree of osteopenia is the only relevant manifestation of the disease. Low bone mineral density (BMD) in patients with PHPT is an indication for surgical intervention because successful parathyroidectomy results in a dramatic increase in BMD. However, low BMD values are almost an invariable finding in elderly women with PHPT, who are often either unwilling or considered unfit for surgery. Bisphosphonates are capable of suppressing parathyroid hormone (PTH)-mediated bone resorption and are useful for the prevention and treatment of postmenopausal osteoporosis. In this pilot-controlled study, we investigated the effects of oral treatment with alendronate on BMD and biochemical markers of calcium and bone metabolism in elderly women presenting osteoporosis and mild PHPT. Twenty-six elderly patients aged 67-81 years were randomized for treatment with either oral 10 mg alendronate on alternate-day treatment or no treatment for 2 years. In the control untreated patients a slight significant decrease was observed for total body and femoral neck BMD, without significant changes in biochemical markers of calcium and bone metabolism during the 2 years of observation. Urine deoxypyridinoline (Dpyr) excretion significantly fell within the first month of treatment with alendronate, while serum markers of bone formation alkaline phosphatase and osteocalcin fell more gradually and the decrease became significant only after 3 months of treatment; thereafter all bone turnover markers remained consistently suppressed during alendronate treatment. After 2 years in this group we observed statistically significant increases in BMD at lumbar spine, total hip, and total body (+8.6 +/- 3.0%, +4.8 +/- 3.9%, and +1.2 +/- 1.4% changes vs. baseline mean +/- SD) versus both baseline and control patients. Serum calcium, serum phosphate, and urinary calcium excretion significantly decreased during the first 3-6 months but rose back to the baseline values afterward. Increase in serum PTH level was statistically significant during the first year of treatment. These preliminary results may make alendronate a candidate as a supportive therapy in patients with mild PHPT who are unwilling or are unsuitable for surgery, and for whom osteoporosis is a reason of concern.     

Prevention of glucocorticoid-induced osteoporosis

There is increasing evidence that pamidronate and related compounds are effective in the prevention and treatment of osteoporosis. It is therefore of relevance to document the time course and mechanism of bisphosphonate action in this condition. To this end, the present study describes the biochemical responses to prophylactic treatment with oral pamidronate (APD, 150 mg/day) in 16 glucocorticoid-treated patients and contrasts them with those in 19 steroid-treated control subjects. Measurements were made over a period of 12 months. The treated patients showed a fall in urine hydroxyproline excretion at 6 weeks associated with a reduction in serum ionized calcium concentration, a rise in serum 1,25-(OH)2D3, and a nonsignificant rise in serum bone gla protein (BGP). In contrast to BGP, serum alkaline phosphatase activity declined at 6 weeks, falling further at 3 months. Between 3 and 12 months, BGP levels paralleled those of alkaline phosphatase and hydroxyproline, all these being significantly below their initial values, and the other parameters returned to baseline. There was a gradual increase in plasma phosphate concentrations in the treated group over the 12 month period. It is concluded that pamidronate produces an acute and sustained inhibition of bone resorption followed by a more gradual reduction in bone formation. This transient dissociation results in a reduction in serum calcium, leading to a rise in serum 1,25-(OH)2D3, which in turn stimulates BGP production. Thereafter, indices of bone turnover remain subnormal but serum calcium and 1,25-(OH)2D3 return to baseline.     

Alteration of the circadian rhythm of intact parathyroid hormone and serum phosphate in women with established postmenopausal osteoporosis

Several studies have established that the circulating concentration of intact parathyroid hormone, PTH (1–84), over 24 h follows a circadian rhythm. The importance of this circadian rhythm is not known although some authors have detected alterations in the rhythm in metabolic bone disease and following dietary manipulation. We have studied the circadian rhythm of PTH (1–84) in 8 premenopausal women, 8 postmenopausal women with established osteoporosis and 8 postmenopausal women with no evidence of osteoporosis. Blood samples were obtained at 30-min intervals over a 24-h period and significant differences were found in the profiles of PTH (1–84) and serum phosphate in the three groups studied. Premenopausal women possessed a nocturnal/early morning increase in PTH (1–84) and phosphate (between 2200 and 0700 hours), as did postmenopausal women without osteoporosis. In postmenopausal women with osteoporosis the nocturnal increase in PTH (1–84) and serum phosphate was absent and PTH (1–84) decreased during the period 2200-0700 hours. A shift in acrophase is observed between premenopausal and postmenopausal women without osteoporosis. No acrophase was found in postmenopausal women with osteoporosis for either PTH (1–84) or serum phosphate. No circadian rhythm, acrophase or significant amplitude was observed in serum adjusted calcium or ionized calcium in any group studied. Alterations in the circadian rhythms for PTH (1–84) and serum phosphate occur in patients with postmenopausal osteoporosis that suggest the normal dynamics of PTH (1–84) secretion may play a role in both calcium and phosphate metabolism and the bone remodelling process. Whether these changes are causative or a response to the pathology will require further investigation.     

Secondary hyperparathyroidism in diabetic and nondiabetic patients on long-term continuous ambulatory peritoneal dialysis (CAPD)

Serum values of calcium, phosphate, alkaline phosphatases and parathyroid hormone (PTH) are reported for 24 diabetic and 26 nondiabetic patients treated with continuous ambulatory peritoneal dialysis (CAPD) for a total of 779 months, without the use of vitamin D or calcium supplements. Radiographic data are reported for 25 patients followed on CAPD for at least 12 months. Serum calcium was well maintained and control of hyperphosphataemia acceptable, but phosphate-binding therapy had to be continued in the majority of patients. Diabetic patients had lower serum phosphate levels and higher serum calcium than nondiabetic patients during the first year of CAPD. In nondiabetic patients the institution of CAPD was followed by a fall in PTH, possibly largely reflecting transperitoneal PTH elimination. No patient achieved normalization of serum PTH on CAPD. Although no symptomatic bone disease was observed, radiographic evidence of progressive hyperparathyroid bone disease developed in 3 of the 25 examined patients, all nondiabetic. In summary, long-term CAPD with a dialysate calcium concentration of 1.75 mmol/l seems to be compatible with normocalcaemia and a steady-state situation with regard to secondary hyperparathyroidism in the majority of patients. Despite transperitoneal elimination, serum PTH remains elevated, and definite progression of hyperparathyroidism is observed in some patients, however, probably making a case for vitamin D therapy and/or intraperitoneal or peroral calcium supplementation in these patients.     

Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients.

BACKGROUND: Cinacalcet rapidly normalizes serum calcium and reduces intact parathyroid hormone (PTH) levels in renal transplant patients with hypercalcaemia and persistent hyperparathyroidism. The aim of this study is to evaluate the 6 months efficacy of cinacalcet and the effect of cinacalcet withdrawal on serum calcium and PTH in such patients. Furthermore, the impact of cinacalcet on bone turnover and quality of life was assessed. METHODS: Twelve renal allograft recipients with hypercalcaemia due to persistent hyperparathyroidism were treated with cinacalcet for 26 weeks. Cinacalcet was then withdrawn to check for recurrence of hypercalcaemia. RESULTS: Cinacalcet maintained normocalcaemia in all patients from week 4 to 26, and PTH significantly decreased and remained suppressed. Serum phosphate increased, whereas the serum calcium-phosphate product remained unchanged. The excretion of calcium and phosphate in the 24 h urine had tendency to decrease. After cinacalcet was withdrawn, hypercalcaemia recurred rapidly and PTH increased to baseline values. Renal function remained stable, proteinuria was unchanged and no allograft rejection was observed. During treatment with cinacalcet, total and bone-specific alkaline phosphatase increased, whereas the urinary deoxypyridinoline-creatinine ratio did not change significantly, suggesting enhanced bone formation. Quality of life assessed at weeks 10 and 26 remained unchanged compared with baseline. CONCLUSIONS: In conclusion, continued treatment with cinacalcet is required to maintain long-term normocalcaemia and to suppress the enhanced PTH production in renal transplant recipients with persistent hyperparathyroidism.     

Biochemical Effects from Treatment with Bisphosphonate and Surgery in Patients with Primary Hyperparathyroidism

Patients with primary hyperparathyroidism (pHPT) are sometimes treated with bisphosphonates (BPs) as an alternative to surgery despite sparse documentation of the efficacy in this disorder. It is therefore of interest to study the biochemical effects from BPs in patients with pHPT. A series of 21 pHPT patients with serum calcium levels > 2.8 mmol/L were included. One month before surgery the patients underwent intravenous infusions of 30 to 40 mg pamidronate. Study parameters were total and ionized serum calcium, intact parathormone (PTH), alkaline phosphatase (ALP) and isoenzymes, creatinine, osteocalcin, 25-OH vitamin D₃, 1,25-OH₂ vitamin D₃, urine calcium/creatinine, and osmolality. Registration of hypercalcemia-related symptoms were done by questionnaire. After pamidronate there was a temporary reduction in serum calcium with a nadir at 6 to 10 days. Normalization of serum calcium was achieved only by surgery. Intact PTH rose after pamidronate, with a maximum on day 6. Urinary calcium excretion was reduced after both pamidronate and surgery. ALP was reduced 30 days after pamidronate and also after surgery. Serum osteocalcin was not influenced by pamidronate. No statistically significant differences in symptoms were reported after treatment. In conclusion, there was a short, limited calcium-lowering effect from pamidronate in pHPT patients and a transient increase in PTH corresponding to the reduced calcium concentration. An obvious change in bone markers was found only after surgery. Treatment with BPs should not be considered an alternative to surgery, which is still the only method to cure patients with pHPT.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden June 14–17, 2004.     

Immunoreactive serum calcitonin and skeletal histology in chronic renal failure

Serum calcitonin and serum parathyroid hormone (PTH) were measured in 50 patients undergoing regular haemodialysis for end-stage chronic renal failure, and an analysis of osteoclast and osteoblast activities was made in bone biopsies obtained by iliac crest trephine. Osteoclast and osteoblast activities were studied in a multivariate analysis in relation to factors which might reasonably be thought to influence activity, namely serum calcitonin, serum PTH, serum calcium, serum inorganic phosphate, and bone aluminium. Only serum PTH correlated strongly with osteoclast activity (p = 0.0047). Serum PTH correlated also with osteoblast activity (p = 0.0024). Serum inorganic phosphate correlated negatively with osteoblast activity (p = 0.0082). Serum calcitonin did not correlate with osteoclast or osteoblast activities but did correlate strongly with bone aluminium in a multivariate analysis (p = 0.0078). Bone aluminium did not correlate independently with osteoclast or osteoblast activities. This study affirms the implied powerful role of PTH in influencing osteoclast and osteoblast activities in end-stage chronic renal failure.     

Bone mass, size, and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy.

Cyclical intravenous therapy with pamidronate improves the clinical course in children and adolescents with osteogenesis imperfecta (OI). In this study, we evaluated the effect of this therapy on lumbar spine bone mass (bone mineral content [BMC]), size (bone volume [BV]), and density (volumetric bone mineral density [vBMD]). Results from 56 patients (age, 0.2-15.9 years; 25 girls) on long-term pamidronate treatment were compared with those of 167 patients who had not received pamidronate before densitometry. In all patients who received pamidronate, BMC, BV, and vBMD increased above levels expected for untreated patients (p < 0.001 in each case). After 4 years of treatment, BMC, BV, and vBMD were 154%, 44%, and 65% higher, respectively, in treated than in untreated patients who were matched for age and OI type. A multiple regression model showed that baseline BMC was negatively associated with the increase in BMC. In conclusion, the bone mass increase in pediatric OI patients receiving pamidronate is caused by increases in both bone size and density. Patients with larger deficits in bone mass at baseline have a more marked bone mass gain during therapy.     

Comparison of the effects of calcitriol and maxacalcitol on secondary hyperparathyroidism in patients on chronic haemodialysis: a randomized prospective multicentre trial.

BACKGROUND: To identify differences between the effects of calcitriol and the calcitriol analogue, maxacalcitol, on parathyroid hormone (PTH) and bone metabolisms, we conducted a randomized prospective multicentre study on patients on chronic haemodialysis. METHODS: We randomly assigned 91 patients with secondary hyperparathyroidism [intact PTH (iPTH) > or =150 pg/ml] to have either calcitriol (47 patients) or maxacalcitol (44 patients) therapy, for 12 months after a 1 month control period. Serum electrolytes, bone alkaline phosphatase (bAP), iPTH, total PTH and PTH(1-84) (whole PTH) levels were measured periodically. The first end point was a serum iPTH of <150 pg/ml, the second was the iPTH levels obtained. RESULTS: Treatment was discontinued for various reasons in nine patients in each group, but no serious side effects were observed in either group. The numbers of cases reaching the first end point were not significantly different between the two groups. Serum calcium concentration was significantly higher in the maxacalcitol than the calcitriol group during early treatment, but not at the end of treatment. Throughout the treatment period there were no significant differences between the two groups in serum iPTH, inorganic phosphate, the product of the serum calcium and inorganic phosphorus concentrations, bAP, or the ratio of whole PTH to total PTH minus whole PTH. Nor were the changes in these parameters significantly different between the two groups comparing the patients with moderate to severe hyperparathyroidism (basal iPTH > or =500 pg/ml). CONCLUSION: Calcitriol and maxacalcitol are equally effective on PTH and bone metabolism.     

Postoperative Elevated Serum Levels of Intact Parathyroid Hormone after Surgery for Parathyroid Adenoma: Sign of Bone Remineralization and Decreased Calcium Absorption

Increased levels of intact parathyroid hormone (PTH) have been documented after surgery for primary hyperparathyroidism (pHPT) despite normocalcemia. The pathogenesis remains to be elucidated. Seventeen consecutive patients operated on for solitary parathyroid adenoma were investigated before and at 8 weeks and 1 year after surgery with serum levels of intact PTH, biochemical variables known to reflect PTH activity, and bone mineral content (BMC). In addition, an oral calcium loading test was performed 8 weeks after the operation. All patients had low or normal serum calcium levels during follow-up. Eight weeks after operation six patients (35%) had an increased serum PTH level. These patients (group I) preoperatively had higher serum levels of PTH and alkaline phosphatase than patients with normal PTH levels (group II). They also had lower BMC and larger parathyroid adenomas. They did not differ in renal function. At 8 weeks after operation group I showed higher mean serum levels of osteocalcin and propeptide of type I procollagen but lower urinary calcium excretion. In contrast to patients in group II, they also showed a lower calciuric response and a trend to a lower calcemic response during the oral calcium load. The two groups showed similar parathyroid sensitivity for calcium. Patients in group I demonstrated a significant increase in BMC the first year after the operation. Increased serum PTH 8 weeks after surgery for sporadic parathyroid adenoma was not due to persistent pHPT or impaired renal function. Instead, the results imply there is diminished calcium absorption and increased bone turnover with cortical bone remineralization.     

Cyclic therapy of osteoporosis with neutral phosphate and brief, high-dose pulses of etidronate

We have designed a cyclic regimen for the treatment of osteoporosis based on the activate, depress, free, and repeat (ADFR) concept. Osteoclastic bone resorption is activated by 7 days of oral neutral phosphate and inhibited with a brief pulse (5 days) of etidronate disodium at a high dose (20 mg/kg body weight). Patients next take calcium supplements for 48 days before resuming phosphate to enter the next cycle. Osteoporotic women increased the bone mineral density of the lumbar spine at 6 months by 7.2 +/- 5.2% (mean +/- SD, N = 14) and at 12 months by 8.2 +/- 4.0% (N = 8). Control observations in regularly exercising postmenopausal women (N = 30) showed no significant change in spine mineral density after 20 months (0.5 +/- 3.2%), confirming the stability of the measurement technique. The two patients who responded poorly to the cyclic regimen each showed a blunted rise in serum PTH during oral phosphate administration, suggesting that the rise in PTH induced by oral phosphate may be an important component of this cyclic regimen. This preliminary study does not identify which component or components of the regimen are responsible for the increase in bone mass but provides positive encouragement for randomized studies designed to determine the optimum dosage, duration, and timing of each component of the regimen.     

The effect of intravenous pamidronate versus oral alendronate on bone mineral density in patients with osteoporosis

Intravenous pamidronate is frequently used for the treatment of osteoporosis in patients who cannot tolerate oral bisphosphonates. The aim of the present study was to compare the changes in bone mineral density (BMD) after 1 year of treatment with either oral alendronate or intravenous pamidronate in patients with osteoporosis. We studied 40 consecutive patients starting treatment for osteoporosis: 20 received oral alendronate 10 mg/day and 20 received intravenous pamidronate 60 mg/3 months. Patients were started on intravenous pamidronate in the case of intolerance (within 1 month of start of treatment) of an oral bisphosphonate or in the case of contraindications for an oral bisphosphonate. BMD (spine and total hip) was measured with dual X-ray absorptiometry (DEXA) at the start of treatment and after 1 year. The BMD of the lumbar spine increased by 4.0% (P<0.05 vs baseline) in both groups, and the BMD of the hip increased by 3.3% and 2.9% (P<0.05 vs baseline) in the alendronate and pamidronate groups, respectively. The increases in BMD of the vertebral spine and the total hip after 1 year are comparable in the alendronate and pamidronate groups. We conclude that intravenous pamidronate can be used successfully as an alternative treatment in patients with gastrointestinal intolerance of an oral bisphosphonate.     

Regulation of calcium absorption by 1,25,dihydroxy-vitamin D--studies of the effects of a bisphosphonate treatment

In 10 patients with Paget's disease of bone and 2 patients with osteoporosis, we studied the effects of hypocalcemia and hypophosphatemia induced by disodium-(3-amino-1-hydroxypropylidene)-1,-bisphosphonate (APD) treatment on the serum concentration of PTH and 1,25-dihydroxy-vitamin D [1,25(OH)2D3] and on calcium absorption and balance. The fall in serum calcium and phosphate was associated with a rise in the serum concentration of PTH and 1,25(OH)2D3, coupled with increases in net calcium absorption and calcium balance. The concentration of 1,25(OH)2D3 was significantly related (P less than 0.001) to the serum calcium (r = 0.66), the serum phosphate (r = 0.78), and the serum PTH (r = 0.71), confirming the interrelated control of these parameters on 1,25(OH)2D3 production. Moreover the rise in 1,25(OH)2D3 caused an appropriate rise in calcium absorption (r = 0.74) and calcium balance (r = 0.86), showing that this vitamin D metabolite contributes as a hormone to calcium homeostasis.     

Hemithyroidectomy: long-term effects on parathyroid function--preliminary report

Early hypocalcemia after thyroid surgery has frequently been reported, whereas data regarding long-term effects on calcium homeostasis are scarce. We have previously studied patients after hemithyroidectomy with an oral calcium load test and found normal parathyroid hormone (PTH) suppression. However, the 1,25-dihydroxyvitamin D concentration was decreased and the phosphate concentration increased, implying parathyroid insufficiency. We therefore proceeded to investigate PTH secretion and suppression in 10 euthyroid patients subjected to hemithyroidectomy due to benign thyroid disease before and at 1 year after surgery. In addition, biochemical variables known to influence calcium homeostasis were analyzed. Basal, maximal, and total PTH secretion were unaltered 1 year postoperatively. However, maximal PTH secretion was reached at a lower serum level of ionized calcium, and there was a tendency toward increased parathyroid sensitivity to ionized calcium. Furthermore, compared to preoperative, total serum calcium, 1,25-dihydroxyvitamin D, and free thyroxine (T4) concentrations were decreased at follow-up. Total serum calcium and 1,25-dihydoxyvitamin D concentrations were decreased 1 year after hemithyroidectomy. These changes were not due to parathyroid insufficiency. Instead, our results imply increased parathyroid sensitivity to calcium and possibly reduced peripheral sensitivity to PTH.     

Parathyroid hormone secretory pattern,circulating activity,and effect on bone turnover in adult growth hormone deficiency

Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Reports have associated parathyroid hormone (PTH) circadian rhythm abnormalities with osteoporosis. Furthermore, there is evidence of relative PTH insensitivity in AGHD patients. Factors regulating PTH circadian rhythm are not fully understood. There is evidence that serum phosphate is a likely determinant of PTH rhythm. The aim of this study was to investigate PTH circadian rhythm and its circulating activity and association with bone turnover in untreated AGHD patients compared to healthy individuals. We sampled peripheral venous blood at 30-min and urine at 3-h intervals during the day over a 24-h period from 1400 h in 14 untreated AGHD patients (7 M, 7 W; mean age, 49.5 +/- 10.7 years) and 14 age (48.6 +/- 11.4 years; P = NS) and gender-matched controls. Cosinor analysis was performed to analyze rhythm parameters. Cross-correlational analysis was used to determine the relationship between variables. Serum PTH (1-84), phosphate, total calcium, urea, creatinine, albumin, type I collagen C-telopeptides (CT(x)), a bone resorption marker, and procollagen type I amino-terminal propeptide (PINP), a bone formation marker, were measured on all samples. Nephrogenous cyclic adenosine monophosphate (NcAMP), which reflects the renal activity of PTH, was calculated from plasma and urinary cAMP. Urinary calcium and phosphate were measured on all urine samples. Significant circadian rhythms were observed for serum PTH, phosphate, CT(x), and PINP in AGHD and healthy subjects (P < 0.001). No significant rhythm was observed for serum-adjusted calcium. PTH MESOR (rhythm-adjusted mean) was significantly higher (P < 0.05), whereas the MESOR values for phosphate, CT(x) (P < 0.05), and PINP (P < 0.001) were lower in AGHD patients than in controls. AGHD patients had significantly lower 24-h NcAMP (P < 0.001) and higher urinary calcium excretion (P < 0.05). Maximum cross-correlation between PTH and phosphate (r = 0.75) was observed when PTH was lagged by 1.5 h in healthy individuals, suggesting that changes in phosphate precede changes in PTH concentration. PTH/CT(x) and PTH/PINP showed maximum correlation when CT(x) (r = 0.68) and PINP (r = 0.71) were lagged by 3 h. In AGHD patients, compared to controls the maximum correlation between PTH/phosphate (r = 0.88, P = 0.007), PTH/CTx (r = 0.61, P = 0.027), and PTH/PINP (r = 0.65, P = 0.028) was observed when the lag time was reduced by 1.5 h in all variables, with changes in PTH and phosphate occurring at concurrent time points. Our data suggest decreased end-organ sensitivity to the effects of PTH in AGHD patients, resulting in a significantly lower NcAMP, low bone turnover, and higher calcium excretion in the presence of significantly higher PTH concentrations. We have also demonstrated that changes in serum phosphate precede those of PTH, which in turn precede changes in bone resorption and formation in healthy individuals. This relationship was altered in AGHD patients. These results suggest a possible role for GH in regulating PTH secretion and the bone remodeling process.     

Prednisolone Induces an Increase in Serum Calcium Concentration: Possible Involvement of the Kidney, the Bone, and the Intestine

To evaluate the early effect of glucocorticoids on calcium metabolism, 15 subjects aged 22–58 years (5 males, 10 females) with chronic glomerulonephritis were orally treated with 40 mg daily of prednisolone. Five of these subjects were diagnosed with nephrotic syndrome and none had a serum creatinine concentration of more than 1.4 mg/dl. Serum specimens and 24-hour urine specimens were obtained just before and 24 hours after a single oral dose of prednisolone. Serum calcium, ionized calcium, phosphate, intact parathyroid hormone (PTH), intact osteocalcin and 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and urinary excretion of calcium, phosphate, and deoxypyridinoline were measured. Both serum calcium and ionized calcium concentrations were significantly increased from 4.39 ± 0.10 to 4.47 ± 0.09 mEq/liter (P= 0.037) and from 2.48 ± 0.04 to 2.55 ± 0.04 mEq/liter (P= 0.002), respectively, 24 hours following a single oral dose of prednisolone. Serum intact PTH concentration slightly decreased, but the difference was not significant by statistical analysis. Serum intact osteocalcin concentration was markedly suppressed. In contrast, no significant changes were observed in urinary excretion of deoxypyridinoline. Serum 1,25(OH)₂D₃ concentration measured in five patients was significantly increased. No significant changes in urinary excretion of calcium was observed in the face of these findings. It thus follows that a single oral dose of prednisolone administration increases serum calcium and ionized calcium concentrations, possibly mediated by suppressed bone formation, increased intestinal absorption of calcium, and impaired urinary excretion of calcium. Received: 19 February 1998 / Accepted: 12 March 1999     

Bone disease in long-term adult kidney transplant patients with normal renal function

BACKGROUND: In successful renal transplantation, the degree of renal function recovery is usually incomplete and information is scarce about the abnormalities of mineral metabolism in long-term adult renal recipients with normal renal function. This study was designed to investigate bone mineral metabolism in patients with a long-term normal functioning kidney. METHODS: Twenty-nine adult asymptomatic renal transplant (RT) recipients with stable graft function for more than 10 years and serum creatinine <2 mg/dL were studied. They were classified into two groups according to glomerular filtration rate: Group A (N = 12; nine men, three women)>70 mL/min (x: 126 +/- 55 mL/min) and Group B (N = 17; nine men, eight women) <70 mL/min (x: 56 +/- 11 mL/min). Circulating biochemical markers of bone remodelling, bone histomorphometry, and densitometry (lumbar spine and hip) were obtained to investigate bone disease in these patients. RESULTS: Serum PTH was slightly elevated in 10 patients (83%) in group A. Serum PTH levels were positively related to serum calcium, osteocalcin, BAP, telopeptide, OH-proline, and creatinine. There was no histologic data to support overactivity on bone in this group of patients, with only one showing high bone turnover. Mineralization was prolonged in 34% of patients. Twenty-two patients (75%) exhibited normal bone turnover. In the group with GFR>70 mL/min the prevalence of mineralization defect in the presence of normal serum levels of calcitriol suggested vitamin D resistance. Lumbar and femoral neck osteoporosis was present in 25% and 33% of patients in group A, and 23% and 53% in group B, respectively. T-score at lumbar spine was negatively correlated with months since transplantation. Patients under treatment with cyclosporine (CsA) showed increased concentrations of osteocalcin and D-pyr and higher lumbar bone mineral density (BMD), but bone histomorphometry was not influenced by CsA. CONCLUSION: Patients with long-term renal transplantation with normal renal function frequently present with slight increases in PTH, but without an effect on bone histology. CsA did not induce changes in bone histology and delayed mineralization was frequently observed.     

Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels

In patients with adynamic bone disease, the bone contains few osteoblasts or osteoclasts and bone turnover is slow, so the risk of fracture is increased. The decrease of bone remodeling may also decrease the capacity of bone to buffer calcium, leading to an increase of the calcium x phosphate product and an increased risk of arterial calcification. Such findings emphasize that an effective treatment for adynamic bone disease is required. The present study investigated the influence of vitamin K2 (menatetrenone) on hemodialysis patients with low serum parathyroid hormone levels by using bone metabolism markers. The subjects were 32 hemodialysis patients (19 men and 13 women) aged from 27 to 76 years with an intact parathyroid hormone (PTH) level of less than 65 pg/ml and an intact osteocalcin level below 20 ng/ml. All patients received oral menatetrenone therapy (45 mg/day) for 12 months. To obtain control data on bone metabolism markers in hemodialysis patients with normal bone turnover, we selected 50 patients who had intact PTH levels within the range that maintains relatively normal bone turnover, that is, from 120 to 250 pg/ml. The baseline levels of all bone metabolism markers were significantly lower in our patients than in the normal PTH control group. There was a significant increase of gamma-carboxyglutamate (Gla) osteocalcin, bone alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase (TRACP), and cross-linked N-terminal telopeptide of type 1 collagen (NTx) levels after vitamin K2 administration. Type 1 procollagen carboxyterminal propeptide (P1CP) and intact osteocalcin both showed a significant increase after 12 months of treatment. Although there was no significant change of the alkaline phosphatase (ALP) level during the 12 months before the start of vitamin K2 therapy, there was a significant increase of alkaline phosphatase after vitamin K2 administration. Adjusted calcium, serum phosphate, and intact PTH showed no significant changes throughout the study. These changes of bone metabolism markers suggested that vitamin K2 therapy can improve bone remodeling in hemodialysis patients with low serum PTH levels.     

Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis

It is well known that long-term glucocorticoid treatment causes osteoporosis, but the precise mechanism remains unclear. Recently, osteoprotegerin (OPG) has been identified as a cytokine that inhibits osteoclast differentiation. We have previously demonstrated that serum OPG is suppressed by glucocorticoids. Therefore, the present study was carried out to clarify the interrelationships between OPG and other markers of bone metabolism during glucocorticoid treatment. Thirteen patients (7 men, 6 women; 44.1 ± 5.9 years old) with chronic glomerulonephritis who were to be treated with glucocorticoids for the first time were chosen for this study. Markers of bone metabolism, including serum OPG, osteocalcin (OC), bone-specific alkaline phosphatase activity (bAP), parathyroid hormone (PTH), tartrate-resistant acid phosphatase (TRAP), and bone mineral density (BMD), were measured before and during the treatment period. Glucocorticoids significantly reduced BMD of the lumbar spine in the 6 month treatment period (p < 0.01). Serum OPG was decreased significantly by glucocorticoids within 2 weeks (p < 0.001), and serum TRAP, a marker of bone resorption, was markedly increased (p < 0.001). On the other hand, there were no remarkable changes in serum PTH. Serum OC and bAP, markers of bone formation, were transiently reduced during the treatment period (p < 0.01). Furthermore, only serum OPG was positively and independently correlated with percentage BMD of age-matched reference (%AMR). These findings imply that glucocorticoid-induced bone loss develops rapidly via enhanced bone resorption and suppressed bone formation. Moreover, the increased bone resorption caused by glucocorticoids may be, at least in part, mediated by inhibition of OPG, not increment of PTH.