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PubMed1982

Bone aluminum and histomorphometric features of renal osteodystrophy.

To evaluate the relationship between aluminum and the characteristics of bone disease in uremia, bone aluminum content and quantitative histomorphometric analysis of bone were evaluated in bone biopsies from 59 uremic patients undergoing maintenance hemodialysis. Biopsies were classified as showing 1) pure osteomalacia (OM) in 23 cases, 2) osteitis fibrosa (OF) in 13, 3) mixed in 7, and 4) mild lesions in 16. There were no significant differences in levels of serum calcium or alkaline phosphatase between the groups, but serum phosphorus levels were slightly higher in those with OF. Serum immunoreactive parathyroid hormone levels were greater in the patients with OF and mixed lesions than in patients with OM or mild lesions (P less than 0.01). Bone aluminum exceeded normal in all groups (P less than 0.01), with values of 175 +/- 18 mg/kg dry wt in OM patients, 46 +/- 7 of OF patients, 81 +/- 29 in mixed subjects, and 67 +/- 7 in patients with mild lesions. Bone aluminum was significantly higher in the OM patients than in any other group (P less than 0.01); also, bone aluminum correlated with the quantitative measure of unmineralized osteoid in OM (r = 0.67; P less than 0.001); no correlations existed for the other groups. There were inverse correlations between bone aluminum and the serum immunoreactive parathyroid hormone (r = -0.35; P less than 0.01) and resorbing surface on biopsy (r = -0.44; P less than 0.001). Bone aluminum correlated with the duration of hemodialysis in patients with OF with mixed and mild lesions (r = 0.49); no relation was seen in OM patients, and bone aluminum was higher for the duration of dialysis, suggesting that aluminum may accumulate more rapidly in OM subjects. These findings are consistent with but do not prove the hypothesis that aluminum plays a pathogenic role in dialysis osteomalacia; the mechanism by which aluminum accumulates remains unknown.

Aluminum↗

PubMed2006

Regression of skeletal manifestations of hyperparathyroidism with oral vitamin D.

CONTEXT: Parathyroidectomy is the only effective therapy for osteitis fibrosa cystica in hyperparathyroidism. OBJECTIVE: The objective of this study was to describe the changes of skeletal and nonskeletal manifestations in a patient with hyperparathyroidism and renal failure after oral vitamin D therapy. DESIGN: This was a descriptive case report. SETTING: The patient was followed up in a referral center. PATIENT: A 55-yr-old male patient with moderate renal failure was referred for expansile lytic lesions affecting several ribs and the spinous process of T12. His creatinine was 1.8 mg/dl; calcium, 8.9 mg/dl; PTH, 666 pg/ml; and 1,25 dihydroxy-vitamin D, 27 pg/ml. Bone mineral density (BMD) Z-scores by dual-energy x-ray absorptiometry were -4.1 at the spine, -1.7 at the hip, and -4.3 at the forearm. MAIN OUTCOME MEASURES: The main outcome measures were the skeletal manifestations of hyperparathyroidism. RESULTS: At 10 months of therapy, calcium level was 10 mg/d, PTH level declined to 71 pg/ml, and BMD increased by 12% at the spine and 18% at the hip. Computerized tomography (CT) cuts revealed marked regression in the lytic lesions. At 2 yr, BMD increased by an additional 6% at the spine, and there were no further changes in the lytic lesions by CT. The vitamin D receptor genotype using the restriction enzymes Bsm1, Taq1, and Apa1 was Bb, tt, and AA. CONCLUSIONS: We showed regression of severe skeletal abnormalities of hyperparathyroidism documented by serial CT images in response to oral vitamin D therapy. It is possible that the vitamin D receptor genotype of the patient modulated this response.

Bone Density↗

PubMed2002

Parathyroid hormone-independent osteoclastic resorptive bone disease: a new variant of adynamic bone disease in haemodialysis patients.

BACKGROUND: Osteitis fibrosa cystica (OFC) caused by secondary hyperparathyroidism is the pre-eminent form of uraemic osteodystrophy. In recent years, however, new bone abnormalities have been described. Among them adynamic bone disease (ABD) has become a focus of growing interest. Marked suppression of dynamic bone measurements with normal or near-normal static bone-forming parameters are the hallmarks of this disorder. Depressed parathyroid hormone (PTH) levels, frequently evident in this entity, have been linked causally with low bone turnover. METHODS: We reviewed bone biopsy specimens from 96 patients with end-stage renal disease undergoing chronic haemodialysis. RESULTS: We found OFC in 50% of our patients, 20% had mixed bone disease, 24% showed bone morphology of ABD and a minority (6%) had osteomalacia, mostly due to aluminium accumulation. In the patients that were affected by ABD there was a distinct subgroup with bone morphology featuring a striking increase in osteoclast number and osteoclast surface, whereas the osteoid volume, osteoid thickness, osteoblast surface, tetracycline uptake and bone formation rates were diminished as in ordinary ABD. Similarly the PTH levels in this subgroup were low or undetectable. CONCLUSION: We describe patients undergoing chronic haemodialysis with static and dynamic bone forming parameters, indistinguishable from that of ABD, but differing from the classic ABD by the presence of increased osteoclastic bone resorption. The suppressed PTH levels in this subgroup suggests that factors other than PTH activate osteoclasts in some patients on chronic haemodialysis. Uraemic cytokines and/or toxic metabolites, including beta-microglobulin, may be involved in this disorder. The precise nature of this bone abnormality remains to be defined by further studies.

Adolescent↗

PubMed1998

Mineralized bone loss at different sites in dialysis patients: implications for prevention.

To characterize the magnitude and location of mineralized bone loss, 40 patients (20 men, 20 women, 29 white, 11 black) with clinically significant renal osteodystrophy who could be unambiguously classified based on histologic criteria as having osteitis fibrosa (OF; 20 cases) or osteomalacia (OM; 20 cases) were studied; they had been on maintenance hemodialysis for 4.6 +/- 3.0 yr. One hundred forty-two healthy women of similar age and ethnic composition served as control subjects. In all subjects, the proportions of mineralized bone, osteoid, and porosity (nonbone soft tissue) were measured separately in cortical and cancellous bone tissue, from intact full-thickness biopsies of the ilium, representative of the axial skeleton. The results were related to the volumes of cortical and cancellous bone tissue separately and to the volume of the entire biopsy core. Approximately three-quarters of the patients had measurements in the appendicular skeleton by single photon absorptiometry of the radius and morphometry of the metacarpal. Disease effects did not differ significantly between ethnic groups. Mineralized cortical bone volume (per unit of core volume) was reduced by approximately 45% in both patient groups. Mineralized cancellous bone volume was significantly increased by 36% in the patients with OF and nonsignificantly reduced by 9% in the patients with OM; however, the reduction in the latter patients was significant in relation to tissue volume. The combined total deficit for both types of iliac bone was approximately 20% in the patients with OF and approximately 40% in the patients with OM. Significant reductions in appendicular cortical bone were demonstrated in both patient groups at both measurement sites. Regardless of the current histologic classification, the major structural abnormality in the skeleton is generalized thinning of cortical bone due to increased net endocortical resorption, the most characteristic effect on bone of hyperparathyroidism. Protection of the skeleton from the adverse consequences of renal failure will require therapeutic intervention in patients with no symptoms of either renal or bone disease.

Absorptiometry, Photon↗

PubMed1979

Azotemic renal osteodystrophy; clinical features and bone pathology.

During the hemodialysis treatment of 543 uremic patients for 10 years, significant complications concerning metabolic calcium disturbances, subperiosteal resorption, calcification of soft tissue or peripheral vessels, and fractures were noted. Significant elevation of alkaline phosphatase was induced for 5 years under hemodialysis using 5.0--6.0 mg/dl dialysate calcium, but not under 7.5 mg/dl dialysate calcium. Plasma immunoreactive parathyroid hormone (iPTH) values were abnormally high with a few exceptions, without relationship to serum calcium levels. Among the patients with chronic renal failure on dietary control, osteomalacic changes were predominant, but their iPTH values were not always elevated. When the patients were treated for a long time with hemodialysis, the mixed type of osteomalacia and osteites fibrosa appeared. Administration of dihydrotachysterol and 1 alpha-hydroxycholecalciferol to the patients on hemodialysis changed the mixed type of osteomalacia and osteitis fibrosa to the osteomalacic type with the marked reduction of osteoid seam thickness.

Adolescent↗

PubMed1981

Comparison of the ultrastructure of a malignant tumor of the mandible containing giant cells with Paget's disease of bone.

Distinction between lesions of the jaws containing giant cells can be difficult. This study reports the results of the study of the ultrastructure of 30 patients with Paget's disease in comparison with a patient diagnosed as having malignant giant cell tumor of the mandible. The ultrastructure of the malignant giant cell tumor of the mandible was found to contain nuclear inclusions morphologically identical with the 12-15 nm tubules characteristic of the nuclei of osteoclasts in Paget's disease of bone. No clinical or laboratory signs of Paget's disease was found in this patient. A search of the literature failed to produce reports of identical nuclear inclusions in soft tissue giant cell tumors, osteosarcomas, reparative granulomas containing giant cells or in osteitis fibrosa cystica. Such nuclear inclusions have been reported in benign giant cell tumors of bone, one another in malignant giant cell tumor and cases of polymyositis. These observations raise the question of a possible virus associated with the tumor since there are recent reports of immunological evidence for the presence of a virus in Paget's disease, and viruses have been suspected in polymyositis.

Adult↗

PubMed1975

Renal osteodystrophy in patients on hemodialysis as reflected in the bony pelvis.

Roentgen studies in a group of 131 patients on maintenance hemodialysis reveal renal osteodystrophy in 25 patients (19 per cent). In 24 patients of the latter group (98 per cent), the various manifestations of renal osteodystrophy appear in the bony pelvis. These include: osteomalacia; osteitis fibrosa; osteosclerosis; dialysis osteopenia; and extraosseous calcifications. Some of the changes, i.e., bending of bone, Looser's lines, metaphyseal fractures and dialysis osteopenia, are due, at least in part, to the weight bearing nature of the bony pelvis. These findings are ararely, if ever, seen in the digits or in other non-weight bearing bones. It is therefore proposed to evaluate the bony pelvis, together with the magnification digital roentgenogram, when a less costly and less time consuming skeletal survey is needed in hemodialized patients.

Adolescent↗

PubMed1998

Is there any association between the presence of bone disease and cumulative exposure to lead?

There is evidence from cell culture experiments, animal studies, and from measurements in humans that lead may exert detrimental effects on bone mineral metabolism. In order to explore a possible association between lead and bone disease, both cortical and trabecular bone lead content as well as serum lead concentration was measured in 117 patients who attended a metabolic bone disease clinic (n = 92) or were undergoing dialysis for renal failure (n = 25). Cortical bone lead content was higher in patients suffering from Paget's disease than it was in controls, patients with osteoporosis, and patients on dialysis. Trabecular bone lead content was lowest in patients with Paget's disease or osteitis fibrosa. There was no association between bone lead content and serum alkaline phosphatase concentration in patients suffering from osteoporosis. No statistically significant differences in serum lead concentrations were found between groups. Our results do not distinguish between the two possibilities that increased bone turnover due to Paget's disease releases lead from trabecular bone which is then available for deposition into cortical bone or the alternative possibility that an increased lead content in cortical bone may cause increased turnover with release of lead from trabecular bone.

Aged↗

PubMed2002

Outcome study of psychological distress and nonspecific symptoms in patients with mild primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism is a common endocrinopathy. The appropriate management of its mild form, however, remains controversial. HYPOTHESIS: Mild primary hyperparathyroidism is associated with psychological distress and other nonspecific symptoms that improve following parathyroidectomy. DESIGN: Two-year prospective before-after study. SETTING: University hospital. PATIENTS: Twenty-six consecutive patients with mild hypercalcemia (<12 mg/dL [<3 mmol/L]) due to primary hyperparathyroidism, without osteitis fibrosa cystica or urolithiasis were enrolled from January 11, 1997, through April 21, 1998. INTERVENTION: Parathyroidectomy. MAIN OUTCOME MEASURES: Primary outcome was psychological distress as measured by the 28-item version of the General Health Questionnaire. Secondary outcomes included body weight, joint pain, and occurrences of bowel movements and urination. RESULTS: Before surgery, 15 patients (58%; 95% confidence interval, 37%-77%) showed psychological distress (case group) while 11 patients did not (noncase group). A clinically and statistically significant reduction in the General Health Questionnaire score was detected at 3 months in the case group (-6.1; 95% confidence interval, -11.0 to -1.2), but the reduction was smaller (-1.9; 95% confidence interval, -6.9 to 3.0) at 24 months after surgery. No significant change in the General Health Questionnaire score was observed in the noncase group during the follow-up. No significant change was noted in any of the secondary outcomes. CONCLUSIONS: Psychological distress was associated with mild primary hyperparathyroidism and was ameliorated after surgery. The improvement, however, was limited in extent and duration.

Aged↗

PubMed1984

Periosteal new bone in uraemic osteodystrophy.

Out of 54 patients requiring haemodialysis approximately one quarter were found to have periosteal new bone associated with severe renal osteodystrophy. This feature has been analysed and correlated with biochemical, clinical, and histological parameters. No direct correlation was found with the duration of haemodialysis, but there is a good correlation with histological indices of osteitis fibrosa and serum parathormone levels. Periosteal new bone regressed or totally disappeared in eight patients after parathyroidectomy and renal transplantation. It is suggested that periosteal new bone may be a useful indicator of hyperparathyroidism in this type of patient.

Adult↗

PubMed1989

Biochemical markers of bone turnover, intact serum parathyroid horn and renal calcium excretion in patients with pseudohypoparathyroidism and hypoparathyroidism before and during vitamin D treatment.

In addition to the well-documented hyporesponsiveness of the kidney, resistance to parathyroid hormone (PTH) has been postulated for bone in pseudohypoparathyroidism type I (PHP). In some of these patients reduced bone density and even frank osteitis fibrosa suggest osteoclastic overactivity. To address the possibility that the skeletal system of patients with PHP may be affected by their increased PTH secretion we measured intact serum PTH and three biochemical markers of bone turnover in a large number of patients with PHP (n = 20). The results were compared with subjects with low (hypoparathyroidism, HP n = 29), normal (controls, n = 31) and high (primary hyperparathyroidism, 1 degree HPT, n = 13) PTH secretion. Both markers of osteoblastic bone formation, alkaline phosphatase activity and osteocalcin concentration in serum, and one index of osteoclastic bone degradation, the urinary hydroxyproline/creatinine ratio (OH-P/Cr), were decreased in HP and increased in 1 degree HPT, whereas only OH-P/Cr was elevated in patients with PHP. Although intact serum PTH was significantly more increased in PHP than in 1 degree HPT, the markers of bone turnover were not significantly different in these two groups, suggesting some bone resistance in the patients with PHP. In these subjects intact serum PTH was elevated even at normocalcaemia during vitamin D treatment with a negative correlation with the respective serum calcium concentration (r = -0.69, P less than 0.001), indicating an elevated set-point for the suppression of their parathyroid glands. OH-P/Cr was negatively related to serum calcium in PHP, it normalized in most patients during normocalcaemia induced by vitamin D treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Surgically induced uremia in rats. I: Effect on bone strength and metabolism.

During the course of chronic renal failure (CRF) in man, renal osteodystrophy (osteitis fibrosa and/or osteomalacia) gradually develops. The present study aimed to establish a similar type of CRF leading to renal osteodystrophy in rats. During progressive CRF development over 225 days after 5/6 nephrectomy, the following serum variables were measured: creatinine, immunoreactive parathyroid hormone (iPTH), 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a25-hydroxyvitamin D3, (25(OH)D3), alkaline phosphatase, albumin, phosphate, urea nitrogen, total calcium, and other blood electrolytes. Subsequent to sacrifice, mechanical properties of the rat femur, bone histomorphometry (osteoid and eroded surfaces) and bone contents of calcium, phosphate and hydroxyproline were also examined. Serum creatinine in rats with CRF gradually escalated by some 70%, while circulating 1,25(OH)2D3 was reduced beneath detection level. Total plasma calcium and phosphate concentrations were, however, almost unchanged indicating that PTH-induced bone remodeling due to moderate hyperparathyroidism sustained calcium homeostasis. Alkaline phosphatase levels were reduced by some 50%, which reflects chronically impeded bone formation. Bone histomorphometry assessment revealed substantial elevation of resorption with moderate accompanying fibrosis in about 70% of afflicted animals. Bone calcium, phosphate and hydroxypyrroline contents remained unaltered. However, hydroxyproline/calcium ratio was marginally reduced. These results, together with altered mechanical bending stress characteristics and diminished diaphysis cross section area, confirm development of mixed bone lesions in the uremic animals. Our results are compatible with the early development of CRF in man. The established rat model is therefore useful in elucidating the precipitation and early treatment of renal osteodystrophy in humans.

Alkaline Phosphatase↗

PubMed1991

Secondary hyperparathyroidism and osteopenia in women following gastric exclusion surgery for obesity.

Gastric exclusion has been introduced as a surgical treatment for morbid obesity. We describe two women who had undergone gastric bypass for obesity with metabolic bone disease and secondary hyperparathyroidism. In one patient transiliac bone biopsy after double tetracycline labelling demonstrated histologic evidence of hyperparathyroidism with osteitis fibrosa cystica. Six additional women who had undergone gastric exclusion were evaluated. Serum phosphorus, calcium, and creatinine were normal in all but one patient who had hypocalcemia. Serum immunoreactive parathyroid hormone was elevated in seven of eight patients and urinary calcium was less than or equal to 2 mmol/d (80 mg/24 h) in 6 patients. Lumbar spine bone mineral density was 86 +/- 7 (mean +/- SE) per cent of predicted and femoral neck bone mineral density was 89 +/- 6 per cent of predicted. Women who have had gastric exclusion for obesity may develop secondary hyperparathyroidism which could result in loss of bone mass.

Bone Diseases, Metabolic↗

PubMedDate not supplied

Differential diagnosis between secondary hyperparathyroidism and aluminum intoxication in uremic patients: usefulness of 99mTc-pyrophosphate bone scintigraphy.

Forty-one patients in chronic end-stage renal failure and 4 patients with a functioning kidney transplant presented with spontaneous hypercalcemia or intolerance to vitamin D3 sterols and/or oral calcium supplements. Bone iliac crest biopsy with aluminum staining and Tc-pyrophosphate bone scintigraphy with determination of Fogelman score were performed in all cases. Two patients had aluminum-induced osteomalacia (AL O). Thirty-eight biopsies showed renal osteodystrophy (secondary hyperparathyroidism or various combinations of osteitis fibrosa and osteomalacia): 19 with positive staining for aluminum (RO + AL) and 19 without aluminum deposits (RO). The series also comprised 2 cases of pure osteomalacia (OM), 2 cases of osteoporosis (OP), and 1 case of osteoporosis with aluminum accumulation (OP + AL). Mean Fogelman score in RO patients (9.1 +/- 0.3) was significantly higher than in all other categories (5.9 +/- 0.5 for RO + AL, and scores ranging from 0 to 8 in the last 7 patients, p less than 0.01). Patients with massive aluminum accumulation in bone (greater than 75% of the total trabecular surface) showed no or very low uptake of the isotope by the skeleton. Fogelman scores of 9 or higher were always associated with histological secondary hyperparathyroidism. 99mTc-pyrophosphate bone scintigraphy is helpful to distinguish aluminum intoxication from secondary hyperparathyroidism in uremic patients.

Adult↗

PubMed1984

Reversible hypertension in primary hyperparathyroidism--pre- and posteroperative blood pressure in 75 cases.

In 75 operatively proved cases of primary hyperparathyroidism (PH) mean systolic and diastolic blood pressure (BP) values were significantly higher pre- than postoperatively. There were 27 patients (36%) who showed hypertension before operation (systolic BP greater than or equal to 150 mm Hg, mean 169 +/- 20 mm Hg). In 20 of these the hypertension was reversible after successful treatment of PH, in seven cases elevated values persisted. The mean age of patients with persisting hypertension was significantly higher than the group with normalization of BP after operation (P less than 0.01). As far as clinical presentation of PH was concerned it were those cases with hypercalcaemic syndrome and with accidentally discovered hypercalcaemia who most often showed hypertension. In cases with recurrent urolithiasis and with osteitis fibrosa as leading symptoms there was no significant increase of hypertension as compared to the whole group. Because of the relatively high incidence of hypertension in PH this possibility should be taken into consideration in each diagnostic clarification of hypertensive patients.

Aged↗

PubMed1996

Retinoids modulate the effect of PTH and calcitriol on EGF receptor expression in UMR 106-01 cells.

Although osteoblast proliferation is a prominent feature of osteitis fibrosa, studies in vitro using osteoblast-like cells have shown that parathyroid hormone (PTH) impairs cell growth. Recent studies in our laboratory have shown that PTH increases epidermal growth factor (EGF) receptor expression in UMR 106-01 osteoblast-like cells, and thus, osteoblast proliferation may occur as a result of an enhanced response of the osteoblast to EGF. In the present studies we investigated the effect of calcitriol and the influence of retinoids on the regulation of EGF receptors. Calcitriol increased 125I-EGF binding 2.5-3-fold after 72 hours of incubation and was maximal at a calcitriol dose of 100 nM. Scatchard analysis showed that this effect was due to increased receptor number. In contrast, all-trans retinoic acid or 9-cis retinoic acid alone, even at 10 microM, caused less than a 50% increase in 125I-EGF binding. However, the effect of calcitriol was totally abolished in the presence of all-trans retinoic acid. 9-cis retinoic acid was equivalent with all-trans retinoic acid in this regard. In the presence of either retinoid, the stimulatory effect of PTH was totally eliminated and EGF binding was actually decreased below control values. Additional studies revealed that retinoic acid decreased PTH-stimulated cAMP generation in a dose-dependent manner. These data are consistent with our previous studies which showed that the effect of PTH on the induction of EGF receptors was mediated by a cAMP-dependent mechanism. The inhibition of the calcitriol effect by retinoids is consistent with the requirement of the retinoid-X-receptor (RXR) for binding of the vitamin D receptor (VDR) to its target sequences in DNA. These data indicate that EGF receptors in UMR 106-01 cells are up-regulated by PTH and calcitriol and that this process can be modulated by retinoids. Retinoids, therefore, may play a major role in the regulation of osteoblast function by PTH and calcitriol.

Animals↗

PubMed1999

[Treatment of secondary and tertiary hyperparathyroidism--surgical viewpoints].

Nearly all patients with chronic renal failure exhibit some degree of secondary hyperparathyroidism (sHPT), defined as parathyroid hyperplasia and elevated serum parathyroid hormone (PTH) levels. Despite improvements in the medical management of patients with sHPT continue to develop progressive bone disease manifested by osteitis fibrosa cystica, soft tissue calcification and myopathy, pruritus, bone and joint pain and calciphylaxis may accompany the bone disorder. When medical therapy fails, parathyroidectomy becomes necessary. This is not sufficiently explained by the failure to administer calcitriol to control serum phosphate and calcium concentration or to deliver sufficient dialysis. The continuous increase of the proportion of patients exhibiting severe uncontrolled HPT with increasing time of dialysis points to a more basic underlying biological problem; an even higher proportion of patients shows also nodular, rather than diffuse hyperplasia. It was commonly believed that after restoration of normal renal function with successful transplantation, the hyperplastic parathyroid glands would involute and return to normal function state. After renal transplantation some patients continue to have a HPT. This disease entity is recognized and termed as tertiary Hyperparathyroidism (tHPT). After establishing a diagnosis of hyperparathyroid bone disease, in patients with sHPT and tHPT a parathyroidectomy (PTX) frequently becomes necessary to decrease the mass of the hyperplastic parathyroid tissue. The surgical procedure remains controversial. Some surgeons prefer subtotal PTX, others prefer total PTX with autotransplantation of a small amount of tissue to the arm, because the transplanted tissue can be removed in the event of a recurrent HPT. Successful surgical intervention for sHPT and tHPT significantly reduces preoperative symptoms and leeds to restoration of bone disease and therefore supports PTX for patients with s and tHPT. In our experience total PTX with autograft has proven to be a satisfactory procedure. Subtotal PTX is also an effective procedure and the choice of operative technique should be left to the surgeon.

Chronic Kidney Disease-Mineral and Bone Disorder↗

PubMed2005

The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism.

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-kappaB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca(2+) diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca(2+) levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6-9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.

Absorptiometry, Photon↗