Management Of Bone Disease Research Articles

The renal dietitian's role in managing hyperphosphatemia and secondary hyperparathyroidism in dialysis patients: A national survey

Purpose: To survey the medical nutrition therapy practices of renal dietitians for the treatment of bone mineral metabolism. Objectives: To obtain data on phosphorus diet prescription levels. To determine allied team involvement for phosphate binder and Vitamin D therapies. To assess the frequency and target levels for monitoring serum calcium, phosphorus, -phosphorus product, intact PTH and alkaline phosphatase. Methods: Two renal dietitians from the National Kidney Foundation-Council on Renal Nutrition developed a 5-question survey. This was posted on both the RenalRD Listserv and the NKF-CRN website from January 1 through February 15, 2001. Dietitians were asked to respond using facsimile, e-mail or reply by mail. Results: One hundred and thirty-one surveys were received representing all major dialysis providers in the United States, the British Virgin Islands, and Japan. Results included information for peritoneal and hemodialysis patients. Five different methods for dosing phosphate binders were determined. Prescribed phosphate binders included calcium acetate, sevelamer hydrochloride, and calcium carbonate. 108 out of 131 dietitian respondents (82.5%) have a medical protocol in place for vitamin D therapy. Of the respondents, 47% were directly responsible for implementing the vitamin D protocol. Paricalcitol was the most widely used form of IV Vitamin D. Biochemistry results were as follows: calcium, 16 different ranges from 8.0 mg/dL to 11.5 mg/dL; phosphorus, 13 different ranges from 2.5 mg/dL to 6.5 mg/dL; calcium-phosphorus product, 13 different ranges from 55-75; iPTH, 20 different ranges from 50-300 pg/mL; alkaline phosphatase, 18 different ranges from no records being monitored to a level of 500 mg/dL. Conclusion: The survey revealed a large variability in the treatment of bone mineral metabolism. Improved clinical practice guidelines for the health care team are being developed with the National Kidney Foundation (NKF)-Kidney Disease Outcomes and Quality Initiative (KDOQI) bone disease management workgroup. © 2003 by the National Kidney Foundation, Inc.

Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions.

A historical look at research in hyperphosphataemia of chronic kidney disease over the last 40 years shows remarkable advances in our understanding of this abnormality and in the technology used to manage it. Phosphate binders, which have become a mainstay in the management of hyperphosphataemia, have evolved from the early use of aluminium gels to calcium salts, to novel, non-absorbed, aluminium-free, calcium-free agents such as sevelamer hydrochloride, and to magnesium-, iron-, and lanthanum-based compounds. With recent advances, clinical management of this complication of chronic renal disease is evolving from adequate care to optimal care, such that new standards in phosphorous management are being set, and various parameters of patient care are being integrated to optimize outcomes and minimize side effects. This paper provides a historical view of the clinical management of hyperphosphataemia, and looks to advances in treatment that are changing the course of renal bone disease management.

Synergistic growth inhibition of YM529 with biologic response modifiers (BRMs) in myeloma cells.

Bisphosphonates (BPs) are effective in the management of bone disease in patients with multiple myeloma. Recent reports have suggested that they may also have an antitumor activity. YM529 is a new synthetic BP with more than 1000 times the bone resorption inhibitory activity of pamidronate. To clarify the direct effects of YM529 on myeloma cells, the cell proliferation and cell cycle perturbation were analyzed using 12 myeloma cell lines established in our laboratory. The growth inhibition was dose dependent. The cells accumulated in [2n<<4n] of the cell cycle and subsequently formed an apoptotic sub-G1 fraction. Combined treatment with all-trans retinoic acid, thalidomide, or interferon-alpha enhanced the growth inhibitory effects of YM529 on these cells. However, there were no remarkable effects of YM529 on the messenger RNA expression for angiogenic factors, cell cycle regulators, or cytokines related to myeloma cells. These results indicate that YM529 is beneficial not only to bone lesions but also for its direct antitumor effects on myeloma cells.

Vitamin K 2 (menatetrenone) for bone loss in patients with cirrhosis of the liver

OBJECTIVE: Bone loss frequently appears in the natural history of liver disease. The effects of therapy for osteoporosis associated with cirrhosis of the liver are still controversial. We evaluated the effects of vitamin K 2 on osteopenia in women with cirrhosis. METHODS: The subjects were 50 women with cirrhosis who had underlying hepatitis viral infections. Half of the patients were randomly assigned to receive vitamin K 2 (menatetrenone). The bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry at entry and at 1-yr intervals for 2 yr. RESULTS: The percentages of change from the initial BMD at 1 and 2 yr after initiation of the study were, respectively, +0.1 ± 2.6% and −0.5 ± 3.5% for the vitamin K 2-treated group and −2.2 ± 2.4% and −4.6 ± 3.9% for the control group. The changes in BMD at each timepoint differed significantly between the control and treated groups ( p = 0.008 for 1 yr and p = 0.002 for 2 yr). In the vitamin K 2-treated group, the ratio of osteocalcin to undercarboxylated osteocalcin in those patients with increases in BMD after 1 yr of treatment was significantly lower than that in patients showing decreases in BMD ( p = 0.017). No adverse effects of vitamin K 2 were noted. CONCLUSIONS: Vitamin K 2 can prevent bone loss and may therefore be useful in the management of bone disease in women with cirrhosis of the liver.

Cyclical etidronate for treatment of osteopenia in patients with cirrhosis of the liver

Osteoporosis is associated with cirrhosis of the liver. We evaluated the effects of cyclical etidronate on osteopenia in women with cirrhosis of the liver. The subjects were 50 women with cirrhosis who had underlying hepatitis viral infection. Half of the patients were randomly assigned to receive cyclical etidronate (200 mg). The bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry at entry and at 1 year intervals for at least 2 years. After 1 year of treatment, the median BMD was +0.7% in the treated group and −2.0% in the control group. After 2 years of treatment, the median BMD was +0.1% in the treated group and −3.4% in the control group. After 3 years of treatment, the median BMD was −0.6% in the treated group and −5.2% in the control group. These differences between the groups were significant. No adverse effects of cyclical etidronate were noted. These results suggest that cyclical etidronate can prevent bone loss and may therefore be useful in the management of bone disease in women with cirrhosis of the liver.

Catabolic and anabolic signals in bone: therapeutic implications.

Bone remodelling accounts for the continuous renewal of the adult skeleton, and its disturbances constitute the pathophysiological basis of most skeletal disorders. Recently identified bone signalling pathways explain the action of known therapeutic agents and provide targets for new developments in the management of bone diseases.

The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma.

Bisphosphonates are effective in the management of bone disease in patients with multiple myeloma and recent reports have suggested that they may also have an anti-tumour activity. In support of this, we have previously demonstrated that bisphosphonates can induce myeloma cell apoptosis in vitro; however, it remains unclear whether this occurs in vivo. We have therefore investigated the effect of the potent bisphosphonate ibandronate in the 5T2MM murine model of established multiple myeloma. Short-term treatment with a high dose of ibandronate had no effect on either myeloma cell number or the proportion of myeloma cells undergoing apoptosis. These observations suggest that although bisphosphonates induce apoptosis in myeloma cells in vitro, they may not have the same anti-tumour effects in vivo.

The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma

Bisphosphonates are effective in the management of bone disease in patients with multiple myeloma and recent reports have suggested that they may also have an anti‐tumour activity. In support of this, we have previously demonstrated that bisphosphonates can induce myeloma cell apoptosis in vitro; however, it remains unclear whether this occurs in vivo. We have therefore investigated the effect of the potent bisphosphonate ibandronate in the 5T2MM murine model of established multiple myeloma. Short‐term treatment with a high dose of ibandronate had no effect on either myeloma cell number or the proportion of myeloma cells undergoing apoptosis. These observations suggest that although bisphosphonates induce apoptosis in myeloma cells in vitro, they may not have the same anti‐tumour effects in vivo.

Bone disease in multiple myeloma.

Bone disease in multiple myeloma.

Effects of peptide fragments of protein kinase C on isolated rat osteoclasts.

The intracellular mechanisms responsible for inhibition of osteoclast activity are of significant interest in the search for more effective ways of managing bone diseases associated with enhanced bone resorption. Previous studies have suggested that the protein kinase C (PKC) pathway is an important inhibitory second messenger in osteoclasts. We, therefore, investigated the effects of the synthetic peptide fragments, PKC(530-558) and (19-36), which correspond to parts of the catalytic and regulatory domains of PKC, on the activity of isolated osteoclasts. These fragments have been shown to activate and inhibit PKC, respectively, in biochemical studies employing isolated rat brain PKC, but have rarely been employed in studies of cellular activity. PKC(19-36), an enzyme inhibitor (PKC-I), had no effect by itself on osteoclastic bone resorption. However, PKC(530-558), a PKC activator (PKC-A), caused a dose-responsive inhibition of bone resorption, which was accompanied by a rapid and distinctive change in osteoclast morphology. This effect was reversible: (a) upon removal of PKC-A, (b) upon continuous exposure to this fragment for more than 36 h, or (c) in the presence of PKC-I. In conclusion, a short synthetic peptide fragment of PKC (PKC-A) significantly inhibits osteoclastic bone resorption; this, together with the fact that the inhibitory effect is abolished in the presence of PKC-I, provides further evidence for an important physiological role for the PKC pathway in the regulation of osteoclast activity. Selective activation of this pathway may have important therapeutic implications for the management of bone diseases associated with enhanced resorption.

Alendronate inhibits osteopontin expression enhanced by parathyroid hormone-related peptide (PTHrP) in the rat kidney.

It has been reported that osteopontin (OPN) plays an important role during urolithiasis as well as bone formation. Generation of stones in the urinary tract may be associated with osteoporosis and bisphosphonates are potent inhibitors of bone resorption, being used with effect in the management of bone disease. We therefore investigated the relationship between alendronate, a bisphosphonate derivative, and OPN expression in the kidney. Alendronate was administered to rats made hypercalcemic by treatment with parathyroid hormone-related peptide (PTHrP). The renal expression of OPN was then evaluated at both protein and mRNA levels. OPN expression was enhanced in the distal tubular cells of hypercalcemic rats and was decreased by alendronate. The observed inhibition of OPN expression suggests an ability of alendronate and other bisphosphonates to act as inhibitors of stone formation in the urinary tract.

Urinary free deoxypyridinoline by chemiluminescence immunoassay: analytical and clinical evaluation

We evaluated an automated chemiluminescence immunoassay (CLIA) developed for the measurement of urinary free deoxypyridinoline (DPD). The new DPD method by CLIA is based on the competition of DPD with particle-bound pyridinoline for a limited amount of monoclonal mouse anti-DPD antibody. Total imprecision (CV) was 3.2-9.0% at 30-270 nmol/L. Regression analysis of urinary DPD concentration (second morning-void) measured by CLIA (y) and enzyme immunoassay (EIA) for adult volunteers (n = 449) with and without bone disease revealed a best fit equation of: y = 1.08 +/- 0.03x - 1.15 +/- 0.98 nmol/L (r = 0.964, S(y/x) = 14 nmol/L). CLIA and EIA methods were correlated with HPLC measurement of urinary free DPD (r = 0.846 and 0.871, respectively). For healthy adults, the creatinine-normalized excretion of DPD (mean +/- SD) measured by CLIA for 61 men (4.1 +/- 1.2 micromol DPD/mol creatinine) and 76 premenopausal women (5.3 +/- 1.8 micromol DPD/mol creatinine) did not differ significantly (P >0.05) from DPD excretion measured by EIA, and both immunoassays showed a significant gender difference (P <0.001) in reference intervals. In a clinical trial, DPD excretion (micromol DPD/mol creatinine) measured by CLIA differed substantially from the reference population for 54 untreated pagetic (12.7 +/- 8.0 SD), 255 untreated osteoporotic (7.5 +/- 4.1), 21 osteomalacic (12.4 +/- 8.5), 17 primary hyperparathyroid (9.4 +/- 4.4), and 14 secondary hyperparathyroid (9.2 +/- 5.1) patients. Clinical sensitivities of the CLIA and EIA methods range from 38% to 80% in bone disorders and limit the use of the DPD measurement in disease detection. DPD excretion after pamidronate treatment in a subgroup of the pagetic patients fell dramatically as assessed by CLIA or EIA. We conclude that the automated CLIA method for DPD is a convenient and reliable method that may aid in the evaluation and management of bone disease and is applicable to high volume testing in the routine clinical laboratory.

A NEW EFFICIENT SYNTHESIS OF ω-AMINOALKYLIDENE-1,1-BISPHOSPHONATE TETRAETHYLESTERS

Bisphosphonates are interesting therapeutic agents in the management of bone diseases and since several years our laboratory has been developing the chemistry of 1,1-bisphosphonates. This paper describes an original synthesis of two aminoalkylidenebisphosphonates by first preparing the intermediate hydroxyalkylidenebisphosphonates which are transformed into amines via the azides.

Degradation Pathways of Salmon Calcitonin in Aqueous Solution

Salmon calcitonin (sCT), a 32-amino-acid peptide, is the active component in many pharmaceuticals used for the management of bone diseases. The degradation pathways of sCT were determined, and the structures of the major degradation products were identified. Aqueous solutions of sCT at pH values of 3, 4, 5, and 6 were degraded, and the major degradation products were detected using reversed phase and size-exclusion high-performance liquid chromatography (HPLC). The degradation rate and pathways of sCT are strongly dependent on pH in the pH range between 3 and 6. The major degradation products were isolated by semipreparative HPLC and identified using a variety of spectroscopic and bioanalytical techniques. The results show that sCT can undergo hydrolyses resulting in cleavage of the 1–2 amide bond and deamidation of the Gln14 and Gln20 residues, sulfide exchange that leads to an unusual trisulfide derivative, and dimerization to reducible and nonreducible dimers. The mechanisms for the pathways can be rationalized from known degradation pathways of peptide and proteins.

Pathogenesis and medical treatment of secondary hyperparathyroidism.

Control of hyperparathyroidism is a major goal of the management of bone diseases in chronic dialysis patients. Severity of hyperparathyroidism has been evaluated mainly by the level of parathyroid hormone (PTH), however, parathyroid size can be another critical marker. Patients with larger parathyroid glands are usually more resistant to calcitriol pulse therapy than those with smaller glands. Large parathyroid glands with nodular hyperplasia are composed of cells more resistant to calcitriol due to lower density of calcitriol receptors. Responsiveness to calcitriol therapy was restored by selective destruction of large parathyroid glands (> 0.5 cm3) by ethanol injections under ultrasonographic guidance. Direct injections of calcitriol solution into enlarged glands were also effective in suppressing PTH and restoring responsiveness to calcitriol. These data suggest that size of parathyroid glands reflects the resistance to calcitriol and that prevention of parathyroid hyperplasia is mandatory for the successful medical management of hyperparathyroidism in chronic renal failure.

Pathogenesis and medical treatment of secondary hyperparathyroidism

Control of hyperparathyroidism is a major goal of the management of bone diseases in chronic dialysis patients. Severity of hyperparathyroidism has been evaluated mainly by the level of parathyroid hormone (PTH), however, parathyroid size can be another critical marker. Patients with larger parathyroid glands are usually more resistant to calcitriol pulse therapy than those with smaller glands. Large parathyroid glands with nodular hyperplasia are composed of cells more resistant to calcitriol due to lower density of calcitriol receptors. Responsiveness to calcitriol therapy was restored by selective destruction of large parathyroid glands (> 0.5 cm3) by ethanol injections under ultrasonographic guidance. Direct injections of calcitriol solution into enlarged glands were also effective in suppressing PTH and restoring responsiveness to calcitriol. These data suggest that size of parathyroid glands reflects the resistance to calcitriol and that prevention of parathyroid hyperplasia is mandatory for the successful medical management of hyperparathyroidism in chronic renal failure. Semin. Surg. Oncol. 13:73–77. © 1997 Wiley-Liss, Inc.

Pathophysiology and Management of Bone Disease in Multiple Myeloma

Pathophysiology and Management of Bone Disease in Multiple Myeloma

Dual-energy X-ray Absorptiometry for the Management of Bone Disease

Professor Emeritus of Medical Physics, University of Wisconsin; and President, Lunar Corporation, Madison, Wisconsin

Interleukin-6 and the acute phase response during treatment of patients with paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate

Bisphosphonates suppress bone resorption and are used in the management of bone diseases with increasing frequency. In some patients treated for the first time with potent nitrogen-containing bisphosphonates, there is a transient febrile reaction and transient hematological changes suggestive of an acute phase response. Because IL-6 is considered to be an important mediator of the acute phase response, we examined the changes in circulating IL-6 bioactivity in 38 patients with Paget's disease treated with the nitrogen-containing bisphosphonate (3-dimethyl-amino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). 16 patients who had never received such bisphosphonate were treated with oral dimethyl-APD (100-400 mg/day) and 22 (9 for the first time) with intravenous dimethyl-APD 4 mg/day. Treatment was given for 10 days. Eleven of 38 patients, all first treatments, showed an increase in body temperature of more than 0.5 degrees C exceeding 37 degrees C associated with a significant decrease in lymphocyte count and an increase in serum CRP values. These changes were transient and did not occur in the patients with no febrile response. In patients with a febrile reaction circulating IL-6 bioactivity increased significantly and this increase generally preceeded the rise in temperature. Moreover, patients with an acute phase response had significantly higher peak IL-6 values than those without (128 +/- 30 vs. 31 +/- 4 U/ml, p < 0.001). The peaks in plasma IL-6 were further correlated with the peaks in temperature and in serum CRP values (r = 0.49, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic osteodystrophy in primary biliary cirrhosis: effects of medical treatment.

Osteoporosis is a frequent extrahepatic complication of primary biliary cirrhosis. Although histologically similar to the osteoporosis commonly seen in postmenopausal females, the pathogenesis and management of bone disease in patients with primary biliary cirrhosis is poorly understood. The experience with a subgroup of patients with primary biliary cirrhosis treated with vitamin D, calcium, and estrogen supplementation was reviewed to determine the effects of medical treatment on hepatic osteodystrophy. The records of 203 women with the diagnosis of primary biliary cirrhosis were reviewed retrospectively for lumbar spine bone mineral density, menopausal status, and supplementation with vitamin D, calcium, and estrogen. The 16 postmenopausal patients treated with estrogen replacement had a statistically significant increase in the lumbar spine bone mineral density at 1 yr (+0.014 +/- 0.049 vs. -0.03 +/- 0.046 g/cm2, p < 0.038), without a significant change in the serum bilirubin or alkaline phosphatase. In treated patients, vitamin D and calcium supplementation did not lead to significant improvement in lumbar spine bone mineral density. Calcium and vitamin D supplementation, even in the presence of vitamin D deficiency, do not improve lumbar spine bone mineral density in patients with primary biliary cirrhosis. Estrogen replacement in postmenopausal patients, however, does appear to improve lumbar spine bone mineral density without increasing clinical or biochemical cholestasis, a potential complication reported in animal studies. This study should serve as an impetus for a controlled trial of estrogen replacement in postmenopausal patients with primary biliary cirrhosis.