Current concepts and management strategies in chronic kidney disease-mineral and bone disorder.

The term renal osteodystrophy describes the pathological changes in bone structure in chronic kidney disease (CKD); however, this term fails to describe adequately the adverse changes in mineral and hormonal metabolism in CKD that have grave consequences for patient survival. CKD-mineral and bone disorder (CKD-MBD) is a broader, newly defined term that should be used instead of renal osteodystrophy to define the mineral, bone, hormonal, and calcific cardiovascular abnormalities that are seen in CKD. The new paradigm in the management of renal bone disease is to "think beyond the bones" and strive to improve cardiovascular outcomes and survival. This means treating other aspects of the disease process that go beyond merely controlling parathyroid hormone levels. Primary physicians need to take a proactive approach to the management of CKD-MBD because the disorder begins early in the course of CKD, well before a patient is referred to a nephrologist. This review outlines the evidence behind the understanding of CKD-MBD, its implications for overall mortality, and the latest recommendations for management of CKD-MBD in patients with predialysis CKD.

Clinical implications of brown tumor uptake in whole-body 99mTc-sestamibi scans for primary hyperparathyroidism.

OBJECTIVES: Technetium-99m (Tc)-sestamibi is the current radionuclide of choice for parathyroid localization in primary hyperparathyroidism (PH). However, there are only sporadic reports about brown tumor visualization in whole-body Tc-sestamibi scans. This study aimed to systematically evaluate brown tumor uptake in whole-body Tc-sestamibi scans and in whole-body bone scans as well. Clinical factors were statistically analyzed for imaging outcome predictions. METHODS: Forty-two patients with PH were recruited consecutively. A dual-tracer, dual-phase parathyroid imaging protocol was applied. A Tc-sestamibi whole-body scan was performed immediately after delayed phase acquisition. A Tc-methylene diphosphonate bone scan was performed on day 3. Parathormone (PTH), calcium, alkaline phosphatase (ALP), and parathyroid lesion volume were compared. The t-test, one-way analysis of variance, and receiver operating characteristic curves were performed for statistical analyses. RESULTS: Brown tumors showed Tc-sestamibi uptake in 10 cases, and Tc-methylene diphosphonate uptake in 17 cases. All parameters in double-scan positive cases were significantly higher than in double-scan negative cases; PTH and ALP were significantly higher in only bone scan positive cases than in double-scan negative cases. Data from receiver operating characteristic curves showed the order of PTH>ALP>Ca>parathyroid lesion volume for diagnostic accuracies of both positive Tc-sestamibi scans and positive bone scans. PTH showed the best positive predictive value and ALP showed the best negative predictive value. CONCLUSION: A Tc-sestamibi whole-body scan could be used to assess brown tumors in PH, although it may be less sensitive than a bone scan. PTH possessed the best diagnostic accuracy and predictive value for a positive imaging outcome. ALP was useful for negative imaging outcome prediction.

Development of renal bone disease.

Renal osteodystrophy (ROD) develops as the early stages of chronic renal failure (CRF) and covers a spectrum of bone changes observed in the uraemic patient, which extend from high remodelling bone disease (frequently known as osteitis fibrosa) to low turnover, or adynamic disease. Between these two extremes there are also cases of bone mineralization compromised in variable degrees, as is the case of 'mixed bone disease' and osteomalacia. The dynamic process of bone remodelling is compromised in CRF, and a positive or negative bone balance can be observed in uraemic patients. In addition to the classic modulators of bone remodelling, like parathyroid hormone, calcitriol and calcitonin, other factors were recently identified as significant modulators of osteoblast and osteoclast activation in uraemic patients. In fact, different cytokines and growth factors, acting at an autocrine or paracrine level, seem to play a relevant role in the bone and mineral changes observed in uraemia. Recently, observations have been made of the development of more sensitive and specific techniques to assay different biochemical markers of bone turnover and mineral metabolism. Analogously, new contributions of conventional bone histology, bone immunocytochemistry and molecular biology, which enabled the understanding of some etiopathogenic mechanisms of ROD, were observed.

[Multiple brown tumours in a patient with tertiary hyperparathyroidism]. / Múltiples tumores pardos en paciente con hiperparatiroidismo terciario.

We describe the case of a 49-year-old female with chronic renal failure and secondary hyperparathyroidism that not dissapeared after kidney transplant and turned into an autonomous form (tertiary hyperparathyroidism). The xRays and CT showed the presence of multiple brown tumors in iliac bones and tibia. We performed a parathyroidectomy removing a lower left adenoma confirmed in the histological exam the renal. After the surgery the osteoarticular manifestations improved and lithiasis dissapeared. There were not any postoperative complications such as hypocalcemia or recurrential palsy although Nephrology Department had to control her renal function.

Oxyphil parathyroid adenoma: a malignant presentation of a benign disease.

Functioning parathyroid adenomas of the oxyphil cell type are rare, and the clinical characteristics of patients with these tumors have not been well defined. We describe two cases of severe primary hyperparathyroidism (PHPT) caused by benign oxyphil parathyroid adenomas. The patients' clinical presentations mimicked parathyroid carcinoma. Both had very large tumors associated with marked elevations in PTH and serum calcium levels. Skeletal manifestations were also atypical for benign PHPT, with severe osteoporosis in one patient and osteitis fibrosa cystica in the other. These cases also highlight the remarkable capacity of the skeleton to recover after successful parathyroidectomy, previously reported in other forms of severe PHPT. Bone mineral density improved dramatically 1 yr after parathyroidectomy, with increases of 51% at the lumbar spine, 36% at the total hip, and 11% at the distal one third radius. Most of the increases occurred in the first postoperative months. Consistent with this early and accelerated skeletal response, markers of bone turnover were increased 2 months after surgery and normalized by 8 months postoperatively. In patients with PHPT who present with severe or atypical clinical features, oxyphil adenoma should be considered.

Cytokine accumulation in osteitis fibrosa of renal osteodystrophy

Bone marrow fibrosis occurs in association with a number of pathological states. Despite the extensive fibrosis that sometimes characterizes renal osteodystrophy, little is known about the factors that contribute to marrow accumulation of fibrous tissue. Because circulating cytokines are elevated in uremia, possibly in response to elevated parathyroid hormone levels, we have examined bone biopsies from 21 patients with end-stage renal disease and secondary hyperparathyroidism. Bone sections were stained with antibodies to human interleukin-1alpha (IL-1alpha), IL-6, IL-11, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-ß (TGF-ß) using an undecalcified plastic embedding method. Intense staining for IL-1alpha, IL-6, TNF-alpha and TGF-ß was evident within the fibrotic tissue of the bone marrow while minimal IL-11 was detected. The extent of cytokine deposition corresponded to the severity of fibrosis, suggesting their possible involvement in the local regulation of the fibrotic response. Because immunoreactive TGF-ß and IL-6 were also detected in osteoblasts and osteocytes, we conclude that selective cytokine accumulation may have a role in modulating bone and marrow cell function in parathyroid-mediated uremic bone disease

Cytokine accumulation in osteitis fibrosa of renal osteodystrophy.

Bone marrow fibrosis occurs in association with a number of pathological states. Despite the extensive fibrosis that sometimes characterizes renal osteodystrophy, little is known about the factors that contribute to marrow accumulation of fibrous tissue. Because circulating cytokines are elevated in uremia, possibly in response to elevated parathyroid hormone levels, we have examined bone biopsies from 21 patients with end-stage renal disease and secondary hyperparathyroidism. Bone sections were stained with antibodies to human interleukin-1alpha (IL-1alpha), IL-6, IL-11, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) using an undecalcified plastic embedding method. Intense staining for IL-1alpha, IL-6, TNF-alpha and TGF-beta was evident within the fibrotic tissue of the bone marrow while minimal IL-11 was detected. The extent of cytokine deposition corresponded to the severity of fibrosis, suggesting their possible involvement in the local regulation of the fibrotic response. Because immunoreactive TGF-beta and IL-6 were also detected in osteoblasts and osteocytes, we conclude that selective cytokine accumulation may have a role in modulating bone and marrow cell function in parathyroid-mediated uremic bone disease.

Primary hyperparathyroidism: pathophysiology and impact on bone.

Primary hyperparathyroidism has been associated with bone loss, especially at cortical skeletal sites. Results from studies evaluating the mineral density of cancellous bone have been more difficult to interpret. Most densitometry studies support the concept that the parathyroid hormone appears to be catabolic at cortical sites and may have anabolic effects at cancellous bone sites. Studies completed to date, however, have been limited by design, definitions of fracture and inadequate control groups. Primary hyperparathyroidism is now increasingly being detected during the asymptomatic phase. The need for parathyroidectomy has been questioned in such patients because there may be no disease progression in the absence of surgery. Medical management of primary hyperparathyroidism has to date been limited to estrogen replacement therapy in postmenopausal women. Identification of the calcium receptor has improved our understanding of calcium homeostasis, and significant reductions in calcium receptor levels have been detected in parathyroid adenomas. Thus, a new class of therapeutics may include the calcimimetic agents. Bisphosphonates are also currently being evaluated with regard to their impact on fracture prevention and their beneficial effects on bone mineral density.

Osteitis fibrosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis.

Pseudohypoparathyroidism is a group of diseases characterized by renal resistance to parathyroid hormone. The patients typically have the bony manifestations of hyperparathyroidism, while being hypocalcemic. Pseudohypoparathyroidism has further been subdivided into types Ia, Ib, Ic, and II. Mutations involving any number of domains of the parathyroid hormone receptor, adenylate cyclase, or G proteins may alter the cellular response to parathyroid hormone. This wide range of possible sites of mutation may explain the heterogeneous biochemical, skeletal, and physical phenotypes associated with the various types of pseudohypoparathyroidism. We describe a patient with pseudohypoparathyroidism who was successfully treated with total parathyroidectomy and gland autotransplantation. The complexities of parathyroid hormone cellular interactions and calcium homeostasis are discussed. Pseudohypoparathroidism is an unusual disease; however, it provides an elegant model for studying problems of calcium balance.

Osteitis fibrosa: treatment trends.

Renal osteodystrophy is frequently seen in patients with end stage renal disease. Osteitis fibrosa associated with secondary hyperparathyroidism is often diagnosed. Treatment options vary based on disease severity. Individual patient considerations need to be addressed to determine the best therapeutic plan. Medical management with calcitriol, dietary modifications, and administration of phosphate binders continues to be the best treatment for most patients. Parathyroidectomy should be reserved for patients with complications related to severe irreversible hyperparathyroidism and/or failure of medical management. Total resection of all parathyroid tissue with or without autotransplant is the most common surgery for hyperparathyroid bone disease.

Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone.

A young girl had tibial osteotomies at age 14 for genu valgum and then had recurrent tibial cysts over a number of years. Hypocalcemia and hyperphosphatemia were first noted at age 21. The diagnosis of pseudohypoparathyroidism was made at age 28, when elevated plasma PTH was detected. Clinical and biochemical features, including a PTH response test and assay of RBC Gs, established the diagnosis of pseudohypoparathyroidism type 1b. Failure to suppress plasma PTH with vitamin D therapy led to an exacerbation of her cystic bone disease; there were widespread lytic lesions radiologically, most of which took up [99mTc]diphosphonate on bone scan. Microradioscopy revealed evidence of resorption of phalangeal tufts. Bone biopsy showed osteitis fibrosa cystica. During an orthopedic procedure, trabecular bone fragments were taken from her right humerus, and bone-derived cells cultured using an explant technique. The cultured cells were osteoblast-like in morphology, fully responsive to PTH, cholera toxin, forskolin, and PGE1 in vitro, and had an alkaline phosphatase and osteocalcin response to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Following this examination of skeletal responsiveness, attempts were made to suppress the elevated plasma PTH levels and symptomatic bone disease by optimizing therapy with oral 1,25-(OH)2D3. When bone pain associated with the cystic bone disease failed to resolve, the patient underwent total parathyroidectomy, following which the bone pain gradually resolved. This is the first direct demonstration of PTH responsiveness in cultured bone cells in the syndrome of pseudohypoparathyroidism with osteitis fibrosa cystica.

Tl-201 uptake in brown tumors of hyperparathyroidism.

Tl-201 chloride bone scans were performed on nine patients with primary hyperparathyroidism just after Tl-201 and Tc-99m parathyroid subtraction scintigraphy. Bone lesions accumulate Tl-201, especially in sites of brown tumor formation. This was proven by the histopathologic examination of two patients. Eight patients had bone scans with Tc-99m MDP. The lesion-to-background ratio was quantified in seven patients for Tl-201 and in four patients for Tc-99m MDP. Tl-201 uptake of the lesions were quantified in two patients. The lesion-to-background ratio was 1.63 +/- 0.21 and 2.51 +/- 0.88 for Tl-201 and Tc-99m MDP, respectively. A Ga-67 citrate scan was performed on one patient, and the lesion-to-background ratio was 1.49 +/- 0.06. The accumulation of Tl-201 in brown tumors of bone might be due to increased blood flow and local metabolic activity. Tl-201 chloride was inferior to Tc-99m MDP in lesion detection. It is concluded that bone imaging with Tl-201 can easily be performed following parathyroid subtraction scintigraphy to delineate the sites of brown tumor formation.

Fractures and vertebral bone mineral density in patients with renal osteodystrophy.

We investigated the relationship of CT determined vertebral bone mineral density (BMD), type of renal osteodystrophy, N terminal PTH levels and fracture history in 31 dialysis patients. BMD for patients with bone biopsy documented osteitis fibrosa was 1.6 standard deviation (SD) above the normal value for age and sex matched controls, while those patients with low turnover osteodystrophy had a mean BMD 1.2 SD below normal (p less than 0.0001). Three patients with osteitis fibrosa who had previously been treated with prednisone had a low BMD (1.8 SD below normal, different than O, p = 0.0015). There was no correlation between BMD and time on dialysis (r = 0.1). An N terminal PTH level greater than 150 pg/ml was a sensitive (94%) and specific (100%) method of separating those patients with osteitis fibrosa from those with low turnover osteodystrophy, while BMD was much less useful in this differentiation. A low BMD was not predictive of fracture history but the type of renal osteodystrophy was. Patients with low turnover osteodystrophy had a fracture rate of 0.2 fractures/dialysis year in comparison to those with osteitis fibrosis who had 0.1 fractures/dialysis year. Patients with the former bone disease fractured mainly axial rather than appendicular bones in contrast to those patients with osteitis fibrosa. In conclusion we found that patients with osteitis fibrosa had increased BMD compared to normal while those with low turnover osteodystrophy had decreased BMD, but that the N terminal PTH level was a better predictor of the type of bone disease present than was BMD.

Renal osteodystrophy: some new questions on an old disorder.

The two major lesions of renal osteodystrophy are osteitis fibrosa cystica (OFC) and osteomalacia (OM). OFC is the characteristic bone lesion of uremic hyperparathyroidism. Although renal failure causes predictable parathyroid hyperplasia, the precise pathogenetic mechanism is still not defined. The "hyperphosphatemia-hypocalcemia-parathyroid hormone (PTH) hypersecretion" sequence of events is no longer an adequate model for the pathogenesis of uremic hyperparathyroidism. Other abnormalities associated with uremia include reduced 1,25-dihydroxyvitamin D (1,25D) synthesis, changes in intracellular phosphorus content or transcellular phosphate fluxes, or alteration in PTH metabolism, eg, change in set-point for PTH secretion. Each abnormality interacts with others and contributes to PTH hypersecretion, but none can completely account for the development and persistence of hyperparathyroidism in renal failure. The possibility that uremia may directly cause parathyroid hyperplasia remains open. It is also possible that factor(s) that initiate hyperparathyroidism may turn out to be quite different from that which sustains the hyperparathyroid state. Although both vitamin D-deficient and vitamin D-resistant OM may develop in patients with renal failure, the majority of uremic OM seen currently is "vitamin D-refractory." Although now there is persuasive evidence implicating aluminum (Al) accumulation as the major pathogenetic cause for the mineralization defect seen in this disorder, additional disturbances may play important contributory roles. Such factors would include extraskeletal effects of Al, differences in host-susceptibility to this element, the localization of Al within bone, uremia per se, and the participation of other metals and toxins. Finally, possible interactions between hyperparathyroidism and OM of uremia are speculated on.

Muramidase, alpha-1 antitrypsin, alpha-1 antichymotrypsin, and S-100 protein immunoreactivity in giant cell lesions.

A spectrum of giant cell lesions was evaluated for muramidase, alpha-1 antitrypsin, alpha-1 antichymotrypsin, and S-100 protein immunoreactivity using an avidin-biotin-complex immunoperoxidase method. Peripheral giant cell granuloma, central giant cell granuloma, giant cell tumor, osteitis fibrosa cystica, cherubism, and giant cell tumor of tendon sheath showed similar patterns of reactivity. Granulomatous inflammatory lesions stained more intensely for muramidase than did noninflammatory lesions. Alpha-1-antichymotrypsin was a slightly better marker of giant cell lesions than was alpha-1-antitrypsin. Positive S-100 protein staining in half the lesions was thought to be due to the presence of Langerhans cells. The results supported the belief that giant cell lesions of bone and tendon sheath are differentiated toward cells of the mononuclear-phagocyte system and that multinucleated giant cells are derived from macrophages.

Parathyroid hormone-like bioactivity in a patient with severe osteitis fibrosa cystica due to malignancy: renotropic actions of a tumour extract as assessed by cytochemical bioassay.

A patient is described with malignancy, hypercalcaemia and radiological evidence of severe parathyroid bone disease but undetectable concentrations of circulating immunoreactive PTH. Autopsy showed the tumour to be a metastatic bronchial carcinoid with no evidence of primary parathyroid disease. Extracts of the tumour had no PTH immunoreactivity but had high concentrations of a substance with identical activity to PTH in a cytochemical bioassay. The biological activity of the extract was not inhibited by PTH antibodies but was inhibited by an antagonist to PTH bioactivity.