Biomedical subjects

H H Malluche

Publications and source records attributed to H H Malluche.

At least 19 recordsLinked to original sources

PubMed2003

Parathyroid hormone assays--evolution and revolutions in the care of dialysis patients.

Renal osteodystrophy may present with low, normal, or high bone turnover. An ideal parathyroid hormone (PTH) assay should discriminate between the bioactive whole PTH-(1-84) molecule and PTH fragments, including the PTH-(7-84) fragment. Most dialysis patients have "intact" PTH (iPTH) levels between 65 and 450 pg/ml, which are poorly predictive of bone turnover state, making the iPTH test of limited value for bone turnover prediction. iPTH levels higher than 500 pg/ml can be observed in some dialysis patients with low bone turnover, while iPTH levels as low as 100 pg/ml have been found in patients with bone turnover above normal, indicating the standard second generation iPTH assay is not a reliable sole indicator of bone turnover. The whole PTH immunoradiometric assay, a third generation assay, uses a detection antibody that recognizes antigenic determinants at the extreme amino-terminal (1-4) end of the PTH molecule, making the assay specific for biologically active whole PTH-(1-84). Comparing results using the whole PTH and iPTH assays, the PTH-(7-84) level is indirectly determined and the PTH-(1-84)/PTH-(7-84) ratio can be calculated. It was shown that PTH-(7-84) inhibits the calcemic effect of PTH-(1-84) and its stimulatory effect on bone turnover. In the interpretation of results using the PTH-(1-84)/PTH-(7-84) ratio, it must be taken into consideration that second generation "intact" PTH assays have different cross-reactivity with PTH-(7-84). Therefore, when comparing or analyzing PTH-(1-84)/PTH-(7-84) ratios, the employed PTH assays must be identical. The whole PTH assay and the PTH-(1-84)/PTH-(7-84) ratio allow more meaningful interpretation of PTH trends, and offer a non-invasive means to more accurately diagnose bone disease in this population.

Chronic Kidney Disease-Mineral and Bone Disorder↗

PubMed2001

Isolation of genomic DNA sequences that bind vitamin D receptor complexes.

Vitamin D signaling is believed to be transduced by a heterodimeric receptor complex that binds to specific sequences of DNA termed vitamin D response elements (VDREs) in the promoter regions of target genes. However, recent studies have suggested that considerable flexibility exists in the types of binding sites the vitamin D receptor (VDR) is capable of recognizing, including some that bind VDR homodimers. In this report, a screening method involving immunoselection and PCR amplification was utilized to examine genomic binding sites for the receptor. Four individual fragments ranging in size from ca. 250-320 bp were nominally isolated from the amplified pool of captured fragments for further analysis. Each of the four sequences was capable of forming specific, unique VDR complexes using recombinant human VDR (rhVDR) alone or rhVDR heteromers formed in conjunction with the addition of recombinant human retinoid X receptor alpha (rhRXRalpha). Two of these fragments exhibited significant hormone-dependent repression of luciferase activity when linked to a thymidine kinase driven reporter vector. DNaseI footprinting revealed specific binding over DR+3 or related half-site sequences found within both of these DNA fragments. The results from this study demonstrate that specific, functional binding sites for the VDR can be successfully isolated from genomic DNA and should aid in the discovery of genes regulated by the steroid hormone.

Animals↗

PubMed2001

Evidence of functional vitamin D receptors in rat hippocampus.

The steroid hormone vitamin D has important biological roles in calcium transport, cell growth, and cell differentiation. Its cellular activities are mediated by high affinity interaction with the vitamin D receptor. In brain, autoradiographic, immunohistologic, and messenger RNA expression studies implicate a number of neuronal systems, including the hippocampus, as potential targets of vitamin D. However, cellular distribution and protein expression, and binding of the receptor to vitamin D response elements have yet to be established in hippocampus. This investigation was undertaken to characterize the vitamin D receptor in rat hippocampus with western blot, immunocytochemistry, and gel shift analyses. The presence of the receptor protein in hippocampus extracts was revealed with western blotting using an anti-rat vitamin D receptor antiserum. In vivo and in vitro immunocytochemical results confirmed the presence of vitamin D receptor in neuronal and glial cells. In the hippocampus, the receptor was localized in pyramidal and granule cell layers, CA1, CA2, and CA3 subfields and in the dentate gyrus. Double labeling for the vitamin D receptor and glial fibrillary acidic protein revealed that glia also expressed the receptor protein. Gel shift analyses evaluated with the murine osteopontin vitamin D response element indicated a specific, bound receptor-containing complex from hippocampal extracts. Altogether, these findings clearly document the localization of vitamin D receptor in rat hippocampus and that hippocampus contains vitamin D receptors capable of specifically binding to DNA. In combination with reports of a neuroprotective role for vitamin D in hippocampal cell survival, these data suggest that the endogenous vitamin D receptor may mitigate processes related to cellular homeostasis, perhaps through a calcium buffering mechanism.

Animals↗

PubMed2001

Improved assessment of bone turnover by the PTH-(1-84)/large C-PTH fragments ratio in ESRD patients.

BACKGROUND: The "intact" parathyroid hormone (PTH) assay recognizes PTH-(1-84) as well as amino terminally truncated PTH fragments, that is, large carboxyterminal PTH fragments (C-PTH fragments). The present study investigated whether the use of the plasma PTH-(1-84)/C-PTH fragment ratio enhances the noninvasive assessment of bone turnover in patients on dialysis. METHODS: Bone biopsies and blood samples for determinations of routine indices of bone turnover and PTH peptides were obtained in 51 adult patients on dialysis not treated with drugs affecting bone such as vitamin D or corticosteroids. Blood levels of large C-PTH fragments were calculated by subtracting PTH-(1-84) from "intact" PTH. Patients were classified according to their levels of bone turnover based on histomorphometrically obtained results of activation frequency. Prediction of bone turnover by the various blood indices was done by using proper statistical methods. In addition, hypercalcemia was induced by calcium gluconate infusion in a subset of patients, and levels of PTH-(1-84), "intact" PTH, and PTH-(1-84)/C-PTH fragment ratio were determined. RESULTS: The PTH-(1-84)/C-PTH fragment ratio was the best predictor of bone turnover. A ratio> 1 predicted high or normal bone turnover (sensitivity 100%), whereas a ratio <1 indicated a high probability (sensitivity 87.5%) of low bone turnover. Calcium infusion resulted in decrease in PTH-(1-84)/C-PTH fragment ratio. CONCLUSIONS: The PTH-(1-84)/C-PTH fragment ratio predicts bone turnover with acceptable precision for biological measurements. Moreover, a change in serum calcium levels is one of the regulators of the relative amount of circulating PTH-(1-84) and its large C-PTH fragments.

Adult↗

PubMed2001

Parathyroid hormone/parathyroid hormone-related peptide type 1 receptor in human bone.

The parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor (denoted as PTH-1R) is a key signaling factor through which calcium-regulating hormones PTH and PTHrP exert their effects on bone. There are contradictory reports regarding the capability of osteoclasts to express PTH-1R. To address this issue in humans, bone biopsy specimen samples from 9 normal controls and 16 patients with moderate to severe secondary renal hyperparathyroid bone disease (2 degrees HPT) with elevated PTH levels were studied to determine whether osteoclasts in the bone microenvironment express PTH-1R messenger RNA (mRNA) and protein. We report that osteoclasts express the PTH-1R mRNA but the protein is detected only in patients with 2 degrees HPT. The PTH-1R mRNA and protein also were found in osteoblasts, osteocytes, and bone marrow cells. Receptor expression was higher in osteoclasts and osteoblasts of patients with 2 degrees HPT than normal controls (98.0 +/- 1.1% vs. 65.7 +/- 14.3% and 65.8 +/- 3.4% vs. 39.1 +/- 6.2%; p < 0.01, respectively). Approximately half of osteoclasts found in bone of patients with 2 degrees HPT have the PTH-1R protein. In patients with 2 degrees HPT, a positive relationship exists between erosion depth, a parameter of osteoclastic activity, and the percentage of osteoclasts with PTH-1R protein (r = 0.58; p < 0.05). In normal controls, an inverse relationship exists between the percentage of osteoblasts with receptor mRNA, mRNA signals/cell, and serum PTH levels (r = -0.82 and p < 0.05 and r = -0.78 and p < 0.01, respectively). The results provide the novel evidence of PTH-1R in human osteoclasts and suggest a functional role for the receptors in 2 degrees HPT.

Adult↗

PubMed2001

Hypercalcemia and human nature.

Patients on hemodialysis may develop severe and symptomatic hypercalcemia if skeletal buffering is ineffective. We report a case of persistent hypercalcemia with apparent extrarenal vitamin D synthesis. Associated aluminium intoxication was suggested on desferrioxamine challenge and adynamic uremic osteodystrophy confirmed on bone biopsy. Plasma calcitriol did not suppress with corticosteroids but did with ketoconazole. No other evidence for underlying granulomatous disease was found. We discuss our approach to less usual causes of hypercalcemia, and emphasise the pitfalls associated with factitious disorders.

Adult↗

PubMed2001

Zinc nutritional status modifies renal osteodystrophy in uremic rats.

BACKGROUND: Previous studies from our laboratories suggested that zinc depletion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25(OH)2D, calcitriol) in calcium- and phosphorus-depleted rats with normal renal function, and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D metabolites, PTH response, mineral balance and bone histomorphometry in animals with different zinc nutritional and renal functional status. METHODS: Fifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -deplete (-) diets for two weeks. Thereafter, half of each paired group underwent nephrectomy (N), while half had sham (S) operations. Animals were observed for eight weeks after surgery. External mineral balances of zinc, calcium, phosphate and magnesium were determined before surgery, and 1, 2 and 7 weeks after surgery. Plasma creatinine, zinc, calcium, phosphorus, magnesium, 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrifice. Static and dynamic bone histomorphometry was determined by standard techniques. RESULTS: After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels, and nephrectomized animals had lower creatinine clearances than respective controls at sacrifice. Plasma calcium and phosphorus concentrations were similar in all four groups at sacrifice. Plasma magnesium concentrations were similar in groups with renal insufficiency, regardless of zinc nutritional status. Plasma 25-hydroxycholecalciferol and calcitriol levels were similar in all groups. There was no difference between mean PTH concentration in sham-operated animals, regardless of zinc nutritional status. Although nephrectomized groups' PTH levels were increased compared to S controls, PTH levels were increased in +Zn/N animals compared to the -Zn/N group. Zinc-deplete groups had consistent negative net zinc balance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of different zinc nutritional status were compared. Nephrectomized animals had histomorphometric changes indicative of higher bone turnover and abnormal mineralization. Zinc deficiency was associated with less evidence of increased parathyroid hormone activity on bone in nephrectomized rats. CONCLUSIONS: Zinc depletion limits the increase in plasma PTH concentration and the expression of secondary hyperparathyroid bone disease during the development of renal insufficiency in the renal ablation model of uremia in rats. The mechanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PTH on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight the potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.

Animals↗

PubMed2000

Molecular bone morphometry.

Quantitative histomorphometric assessment of bone biopsies represents a powerful and informative method for the study of metabolic bone diseases. It is the gold standard against which the noninvasive "diagnostic" markers of bone metabolism as well as newly available therapeutic modalities are tested. With the rapid progress in technology of molecular biology, identification of systemic and local biomolecules known to regulate bone metabolism can now be achieved. The study of localization, levels of expression, and synthesis of these factors in bone and its microenvironment is possible through applications of in situ hybridization histochemistry (ISHH) and immunohistochemistry (IHC). Application of ISHH allows study of specific mRNA expression. IHC determines the presence and distribution of target protein in cells. These two methodologies provide the link between the cellular processes of mRNA transcription and translation to the working protein. Combining the established bone histomorphometric techniques with ISHH and IHC elevates the study of bone to new heights, i.e., cellular and molecular mechanistic issues can now be studied.

Bone and Bones↗

PubMed2000

Vitamin D receptor interactions with positive and negative DNA response elements: an interference footprint comparison.

Interference footprinting protocols were utilized to examine the interactions of the vitamin D receptor (VDR) with either a positive or a negative vitamin D response element (VDRE). A sequence from the human osteocalcin (hOC) gene was chosen for the prototypical positive DR+3 VDRE, while an analogous sequence linked to the avian parathyroid hormone gene (aPTH) was used as the negative VDRE. Both types of response elements were examined for phosphate backbone contacts, as well as base-specific interactions with guanine and thymine residues. Sources of VDR included partially purified canine intestinal preparations, as well as extracts of recombinant human VDR and retinoid X receptor alpha prepared from baculovirus-infected Sf9 insect cells. Cold competition experiments using variable amounts of these oligonucleotides in the mobility shift assay revealed that the hOC element was a five-fold better competitor for heterodimer complex binding than the negative VDRE. Interference footprints revealed extensive strong contacts to the phosphate backbone and individual guanine and thymine nucleotides of the hOC element. The composite hOC footprint was asymmetric for the number and strength of interactions observed over each of the respective direct repeat half-sites. In contrast, the aPTH VDRE footprints revealed fewer points of DNA contact that were limited to the hexanucleotide repeat regions and were strikingly weaker in nature. The alignment of DNA contact points for both elements produced a 5' stagger that was indicative of successive major groove interactions, and consistent with dimer binding. DNA helical representations indicate that the heterodimer contacts to these response elements are substantially different and provide insight into functional aspects of each complex.

Animals↗

PubMed2000

Characterization of vitamin D receptor immunoreactivity in human bone cells.

The present study examined the expression of the vitamin D receptor (VDR) in adult human bone by immunohistochemical analysis. Antiserum from goats immunized with an N-terminal rat VDR peptide was purified by affinity chromatography. The purified antiserum recognized both endogenous rat and recombinant human VDR in Western blots. The purified antiserum was also able to specifically supershift the recombinant human VDR when analyzed in mobility shift assays. Immunohistochemical analysis of MG-63 cells, a human osteoblastic cell line known to express the VDR, revealed prominent staining over the nuclei of these cells. Immunostaining was greatly attenuated in the presence of an excess of the immunizing peptide. Analysis of bone biopsy samples from 16 normal human subjects immunostained for VDR protein showed strong, immunopositive staining over bone cells, particularly osteoblasts, in keeping with prior studies. In addition, there was significant immunoreactivity observed in nuclei of osteoclasts, lining cells and scattered bone marrow stromal cells of the adult human bone. Results showed that 298 osteoblasts out of 808 (36.9%) examined were immunopositive. It was also observed that 29 osteoclasts out of 125 (23%) contained VDR immunoreactivity. The ability to detect VDR in osteoclasts and stromal cell populations suggests that in addition to regulating osteoblast function, these other cell types are also direct targets of the hormone's action. These results demonstrate the utility of this purified antiserum in detecting the VDR in a variety of molecular techniques and should prove useful in examining receptor expression in various pathological conditions.

Adult↗

PubMed2000

Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation.

Insulin-like growth factor I (IGF-I) is an important growth factor for bone, yet the mechanisms that mediate its anabolic activity in the skeleton are poorly understood. To examine the effects of locally produced IGF-I in bone in vivo, we targeted expression IGF-I to osteoblasts of transgenic mice using a human osteocalcin promoter. The IGF-I transgene was expressed in bone osteoblasts in OC-IGF-I transgenic mice at high levels in the absence of any change in serum IGF-I levels, or of total body growth. Bone formation rate at the distal femur in 3-week-old OC-IGF-I transgenic mice was approximately twice that of controls. By 6 weeks, bone mineral density as measured by dual energy x-ray, and quantitative computed tomography was significantly greater in OC-IGF-I transgenic mice compared with controls. Histomorphometric measurements revealed a marked (30%) increase femoral cancellous bone volume in the OC-IGF-I transgenic mice, but no change in the total number of osteoblasts or osteoclasts. Transgenic mice also demonstrated an increase in the osteocyte lacunea occupancy, suggesting that IGF-I may extend the osteocyte life span. We conclude that IGF-I produced locally in bone osteoblasts exerts its anabolic effect primarily by increasing the activity of resident osteoblasts.

Animals↗

PubMed2000

Short-term administration of the bisphosphonate ibandronate increases bone volume and prevents hyperparathyroid bone changes in mild experimental renal failure.

BACKGROUND: Bisphosphonates (BP) are potent antiresorptive agents that have been used successfully in several bone diseases associated with hyperresorption. Hyperresorption, hypercalcemia, and osteoporosis are frequent findings in patients with renal failure or after renal transplantation. The present study was carried out to determine the effects of a new BP, ibandronate, on bone in a state of normal vs. moderately impaired renal function. MATERIAL AND METHODS: Forty 90-day-old female rats were either 2/3 nephrectomized (Nx, n = 20) or sham-operated (Sham, n = 20). Half of the Nx and Sham rats received either ibandronate (1.25 microg/rat s.c.) or vehicle once weekly for three weeks. Before euthanasia, blood drawings were performed and 24-hr urine was collected. Femurs were analyzed by bone histomorphometry. RESULTS: Serum creatinine, parathyroid hormone, and osteocalcin levels were equally higher in Nx rats given ibandronate or vehicle than in Sham rats. There was no difference in serum calcium, phosphorus, alkaline phosphatase, and urinary creatinine among the groups. Ibandronate-treated rats had lower urinary calcium and deoxypyridinoline crosslink levels than their Sham counterparts. Ibandronate-treated rats had higher bone volume than vehicle-treated animals. Ibandronate prevented the increase in erosion depth and bone turnover in Nx rats. CONCLUSIONS: BPs such as ibandronate represent potentially useful tools in the treatment of certain facets of renal bone disease. Indications for BP therapy may include treatment of osteoporosis, hypercalcemia, and/or extraosseous calcifications. Optimal dose and frequency of BP administration need to be determined in these patients.

Alkaline Phosphatase↗

PubMed2000

Hyperphosphatemia: pharmacologic intervention yesterday, today and tomorrow.

Control of serum phosphorus continues to be of utmost importance in renal replacement therapy, due to the high prevalence of hyperphosphatemia in the dialysis population. Hyperphosphatemia has traditionally been associated with secondary hyperparathyroidism, soft tissue calcification, and renal osteodystrophy. Recent evidence implicates poor phosphorus control as an important factor in the development of cardiovascular calcification, cardiac disease, and death in patients with chronic renal failure. Dietary restriction of phosphorus, while an important factor in the control of serum phosphorus, has practical problems that limit its success in most patients. Aluminum was used in the past to inhibit phosphorus absorption, but its accumulation has serious, toxic effects on bone. Calcium-based binders have largely replaced aluminum; however, these binders are limited by the excessive amounts of calcium absorbed, which can frequently lead to positive calcium balance, suppression of bone turnover, and hypercalcemia. Calcium overloading is also associated with soft tissue and cardiovascular calcification. More recent strategies for managing hyperphosphatemia and renal bone disease include the use of nonabsorbed phosphate binders that are aluminum- and calcium-free and the development of vitamin D analogs that control parathyroid hormone activity with less calcemic effects. Future goals include defining optimal target levels of phosphorus, calcium, and parathyroid hormone and developing clinical approaches that will promote parathyroid glands, bone, and cardiac health.

Chronic Kidney Disease-Mineral and Bone Disorder↗

PubMed1999

22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure.

BACKGROUND: Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. METHODS: Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. RESULTS: In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. CONCLUSIONS: These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease.

Animals↗

PubMed1999

The role of bone biopsy in clinical practice and research.

Survival rates of patients on dialysis have increased with improved dialytic therapy. However, the resultant increased duration of dialysis has led to a rise in renal osteodystrophy (ROD). Because this metabolic bone disease can produce fractures, bone pain, and deformities late in the course of the disease, prevention and early treatment are essential. Types of ROD include predominant hyperparathyroid bone disease, low turnover bone disease (including osteomalacia and adynamic bone disease), and mixed uremic osteodystrophy. Serum PTH levels are commonly used to assess bone turnover in dialyzed patients. However, a recent study in our laboratory found that serum PTH levels between 65 and 450 pg/ml seen in the majority of dialysis patients are not predictive of the underlying bone disease. To date, bone biopsy is the most powerful and informative diagnostic tool to provide important information on precisely the type of renal osteodystrophy affecting patients, the degree of severity of the lesions, and the presence and amount of aluminum deposition in bone. Bone biopsy is not only useful in clinical settings but also in research to assess the effects of new therapies on bone. The methods of in situ hybridization histochemistry (ISHH) and immunohistochemistry (IHC) are providing the means to study local biomolecules that play a role in bone metabolism. As these research tools become more refined, they will become increasingly valuable in the study of bone. Alternatives to the bone biopsy continue to be pursued, but they have not been proven to have the same specificity or sensitivity to effectively determine the potential value of a specific therapeutic regimen.

Animals↗

PubMed1999

Intermittent and continuous administration of the bisphosphonate ibandronate in ovariohysterectomized beagle dogs: effects on bone morphometry and mineral properties.

Bisphosphonates have emerged as a valuable treatment for postmenopausal osteoporosis. Bisphosphonate treatment is usually accompanied by a 3-6% gain in bone mineral density (BMD) during the first year of treatment and by a decrease in bone turnover. Despite low bone turnover, BMD continues to increase slowly beyond the first year of treatment. There is evidence that bisphosphonates not only increase bone volume but also enhance secondary mineralization. The present study was conducted to address this issue and to compare the effects of continuous and intermittent bisphosphonate therapy on static and dynamic parameters of bone structure, formation, and resorption and on mineral properties of bone. Sixty dogs were ovariohysterectomized (OHX) and 10 animals were sham-operated (Sham). Four months after surgery, OHX dogs were divided in six groups (n = 10 each). They received for 1 year ibandronate daily (5 out of 7 days) at a dose of 0, 0.8, 1.2, 4.1, and 14 microg/kg/day or intermittently (65 microg/kg/day, 2 weeks on, 11 weeks off). Sham dogs received vehicle daily. At month 4, there was a significant decrease in bone volume in OHX animals (p < 0.05). Doses of ibandronate >/= 4.1 microg/kg/day stopped or completely reversed bone loss. Bone turnover (activation frequency) was significantly depressed in OHX dogs given ibandronate at the dose of 14 microg/kg/day. This was accompanied by significantly higher crystal size, a higher mineral-to-matrix ratio, and a more uniformly mineralized bone matrix than in control dogs. This finding lends support to the hypothesis that an increase in secondary mineralization plays a role in gain in BMD associated with bisphosphonate treatment. Moreover, intermittent and continuous therapies had a similar effect on bone volume. However, intermittent therapy was more sparing on bone turnover and bone mineral properties. Intermittent therapy could therefore represent an attractive alternative approach to continuous therapy.

Animals↗

PubMed1999

Calcific uremic arteriolopathy in association with low turnover uremic bone disease.

We report seven cases (out of 100 dialysis patients) at the University of Kentucky who were diagnosed with calciphylaxis syndrome between 1993 and 1998. Of note is the fact that five of these patients had bone biopsy-proven adynamic renal bone disease, rather low intact PTH, and relatively low calcium-phosphorus product. This is in contrast to the previous view that calciphylaxis is usually seen in patients with excessive parathyroid activity. The reemergence of calciphylaxis with renal bone disease is an intriguing finding and does not correspond to earlier reports associating calciphylaxis with hyperparathyroid bone disease. This report reviews the clinical, biochemical, and bone histology findings of these patients, and provides a review of the literature.

Adult↗

PubMed1999

Understanding and managing hyperphosphatemia in patients with chronic renal disease.

Controlling serum phosphorus levels continues to be a challenge in patients with chronic renal disease. Hyperphosphatemia is implicated in the development and worsening of secondary hyperparathyroidism and renal osteodystrophy (ROD) through its effects on serum calcium and calcitriol levels, parathyroid hormone (PTH) overproduction, and parathyroid cell hyperplasia. In the past serum phosphorus control with aluminum-containing phosphate binders was associated with insidious but serious development of aluminum toxicity. More recent approaches using non aluminum-containing calcium salts as phosphate binders are limited because of the excessive calcium load resulting from concomitant enhanced intestinal calcium absorption. Moreover serum phosphorus does not only result from dietary phosphate intake but also from enhanced bone breakdown due to secondary hyperparathyroidism. Strategies for managing ROD including early control of serum phosphorus and PTH, prevention of parathyroid hyperplasia; establishment of optimal PTH levels for bone health, and the availability of new therapeutic tools for controlling phosphorus may help prevent complications and improve patient outcomes.

Chronic Kidney Disease-Mineral and Bone Disorder↗