Aiji Yajima

Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism

BACKGROUND Successful parathyroidectomy for secondary hyperparathyroidism alleviates bone pain and is followed by the development of hypophosphatemia and hypocalcemia, as well as an increase in bone mineral density. An increase in osteoblast surface (Ob.S/BS) is not observed several months after surgery. In this study, we investigated early bone changes at 1 week after parathyroidectomy and the mechanism underlying an increase in bone mineral density. METHODS Fourteen patients with severe secondary hyperparathyroidism underwent iliac bone biopsy before and 1 week after parathyroidectomy. Changes in histomorphometric parameters, including osteoclast surface (Oc.S/BS), eroded surface (ES/BS), erosion depth (E.De), fibrosis volume (Fb.V/TV), Ob.S/BS, osteoid volume (OV/BV), osteoid surface (OS/BS), and osteoid thickness (O.Th), were investigated. Changes in texture of mineralized bone and osteoid seams were also investigated. RESULTS Oc.S/BS (P < 0.001), ES/BS (P < 0.01), and E.De (P < 0.001) decreased, but Fb.V/TV did not change at 1 week postoperatively. In particular, osteoclasts disappeared in almost all patients. Ob.S/BS (P < 0.001) increased, and cuboidal osteoblasts were proliferating on the trabecular surface where osteoclasts had existed before parathyroidectomy. As a result, newly developed osteoblasts coexisted with fibrous tissue after surgery. OV/BV (P < 0.005), OS/BS (P < 0.005), and O.Th (P < 0.005) increased, with lamellar osteoid volume showing a particular increase. Bone mineralization continued despite the low postoperative serum parathyroid hormone level. CONCLUSION A rapid decrease in serum parathyroid hormone level after parathyroidectomy appears to suppress bone resorption, as well as cause a transient marked increase in bone formation and an increase in normal lamellar osteoid seams.

Increased Osteocyte Death and Mineralization Inside Bone After Parathyroidectomy in Patients With Secondary Hyperparathyroidism

In order to gain insight into the mechanisms underlying the dynamic changes in bone metabolism and bone quality after parathyroidectomy (PTX) in secondary hyperparathyroid patients with high levels of parathyroid hormone (PTH), we performed bone histomorphometric analysis with tetracycline labeling in iliac bone biopsy specimens taken before and after PTX, with special attention paid to osteocytes. At 2 to 4 weeks after PTX, PTH concentrations decreased markedly with evident reductions in bone turnover markers. Histomorphometry revealed that at 2 to 4 weeks following PTX, the osteoclast surface decreased to nearly 0%, with a substantial increase in osteoid volume and a reduction in fibrosis volume. Labeling with tetracycline was observed not only at the mineralization front on the bone surface but also around the osteocyte lacunar walls and canaliculi within both the basic multicellular units (BMUs) and bone structural units (BSUs), suggesting that mineralization was taking place along the lacunocanalicular system after PTX. The tetracycline‐labeled area was much greater in the BSUs than in the BMUs and at the mineralization front, and the tetracycline labeling in the BSUs was markedly increased after PTX compared with that in the low‐ and high‐PTH control groups without PTX. The osteocyte number was decreased significantly after PTX, concomitant with an increase in the number of empty lacunae and a reduction of lacunar volume. Thus the increased osteocyte death and mineralization around the lacunocanalicular system in association with a rapid decline in PTH may underlie the changes in bone metabolism and quality that occur following PTX.

Bone formation by minimodeling is more active than remodeling after parathyroidectomy

Bone formation using the process known as minimodeling forms only lamellar bone in the absence of prior bone resorption even in uremic patients. In patients undergoing parathyroidectomy for secondary hyperparathyroidism, we compared the contribution of minimodeling to remodeling during the change in bone volume. Iliac bone biopsies were used to measure parameters related to minimodeling and remodeling before, at 3 to 4 weeks and 10 to 12 weeks after parathyroidectomy. Osteoblast surface due to minimodeling was greater than the entire bone osteoblast surface before and at 10 to 12 weeks after parathyroidectomy, but not 3 to 4 weeks after surgery. Minimodeling significantly increased osteoid volume 3 to 4 weeks after parathyroidectomy. The rate of change of osteoid volume by minimodeling was greater than that of osteoid volume during the first 3 to 4 weeks after surgery, indicating osteoid formation was more active at the minimodeling surface than at the entire bone surface. Furthermore, higher mineral apposition rates at the minimodeling sites than at remodeling sites yielded increased minimodeling bone volume at 10 to 12 weeks after surgery. Our results show that bone formation by minimodeling is more active than by remodeling and accounts, in part, for the increase of bone volume following parathyroidectomy.

Impact of Cinacalcet Hydrochloride on Bone Histology in Patients with Secondary Hyperparathyroidism

Serum parathyroid hormone (PTH) levels are effectively decreased by cinacalcet hydrochloride (HCl) in patients with secondary hyperparathyroidism. We assessed the impact of cinacalcet HCl on bone histology in these patients. Four hemodialysis patients with secondary hyperparathyroidism (intact PTH ≥ 300 pg/mL) were treated with cinacalcet HCl with low‐doses of vitamin D sterols as well as calcium‐based phosphate binders for 52 weeks. Patients 1, 2, 3 and 4 were aged 55, 65, 61 and 70 years old, and the duration of hemodialysis in the patients was 84, 176, 125 and 216 months, respectively. Serum intact PTH, serum bone metabolism markers and bone histomorphometric parameters were determined before and after 52 weeks of the treatment. Serum intact PTH decreased from 1110, 880, 330 and 980 pg/mL to 233, 80, 88 and 116 pg/mL, respectively, in the four patients after 52 weeks of treatment with cinacalcet HCl. Serum levels of bone metabolism markers and all of the histomorphometric resorption parameters decreased in these patients. In particular, fibrosis volume decreased to 0% in all of the patients. Static formation parameters, including osteoblast surface and osteoid‐related parameters, all decreased after the treatment, indicating an increase of mineralized bone volume during the treatment. Dynamic parameters except for activation frequency decreased after the treatment, indicating significant suppression of bone turnover. Cinacalcet HCl with low‐doses of vitamin D sterols suppressed serum PTH with no significant changes of serum calcium levels. In addition, long‐term administration of cinacalcet HCl improved hyperparathyroid bone diseases in patients with secondary hyperparathyroidism.

Development of low-turnover bone diseases after parathyroidectomy and autotransplantation

Abstract Parathyroidectomy and immediate autotransplantation (PTX‐AT) has been shown to decrease bone pain and increase bone mineral density. However, adynamic bone disease (ABD) has been predicted to develop if the serum intact parathyroid hormone (i‐PTH) level remains lower than normal for a long period of time. Therefore, we investigated the bone histology of patients whose serum i‐PTH levels did not increase over 70 pg/mL for 1 year after PTX‐AT. Four chronic hemodialysis patients were investigated. The serum intact osteocalcin (i‐OC) level was measured and histomorphometry for cancellous bone was performed 1 year after the operation. Tetracycline hydrochloride was administered in the 12 weeks after PTX‐AT. The serum i‐PTH levels were 20.5 ± 15.0 pg/mL and i‐OC levels were 19.5 ± 0.9 ng/mL. Histomorphometric analyses showed the osteoclast surface to be 0.1% in two cases and 0% in the other two cases, the eroded surface was 7.7 ± 6.1%, and the fibrosis volume and osteoblast surface were 0% in all four cases. Osteoid volume, osteoid surface and osteoid thickness were lower in cases 1–3, but higher in case 4. All tetracycline labelings were in contact with the mineralization front in cases 1 and 3, but some were not in cases 2 and 4. Serum i‐PTH and i‐OC levels indicated that ABD developed in these four cases. Histomorphometric analyses revealed that ABD developed in case 1, while either ABD or low‐turnover osteomalacia developed in cases 2 and 4, and low‐turnover osteomalacia was observed in case 3 after PTX‐AT. In conclusion, i‐PTH should not be maintained at lower levels to avoid low‐turnover bone diseases.

Impact of lanthanum carbonate on cortical bone in dialysis patients with adynamic bone disease.

Among the most serious problems in patients with chronic kidney disease (CKD) is fragility of cortical bone caused by cortical thinning and increased cortical porosity; the cortical fragility is sometimes irreversible, with fractures generally initiating from cortical bone. Therefore, development of treatments for problems of cortical bone is urgently desired. Cortical bone has the three surfaces, including the periosteal surface, intracortical spaces and endocortical surface. Bone turnover at the endocortical surface and intracortical resorption spaces are increased as compared with that at cancellous surface. Bone growth sometimes depends on apposition at the periosteal surface.

Characteristics of Patients on Hemodialysis Therapy for More Than 30 Years

Abstract:  Since its experimental introduction in 1960, hemodialysis has become a widely performed and relatively safe procedure. Therapeutic strategies have been developed, and the numbers of long‐term survivors of hemodialysis therapy have been increasing. Hemodialysis therapy was introduced at Sangenjaya Hospital in October 1970, and the 16 patients who have survived for more than 30 years on hemodialysis therapy since its introduction at the hospital were enrolled in this study to investigate the characteristics of long‐term hemodialysis patients. For comparison, 50 patients on hemodialysis for less than 30 years were also studied (21 patients with <10 years hemodialysis, 13 with 10–20 years hemodialysis and 16 with 20–30 years hemodialysis). Background information (age, gender, and cause of renal disease), dialysis dose (single pool [sp.] Kt/V), mineral metabolism (serum phosphate), anemia management (serum hemoglobin), and nutrition (serum albumin and reduced interdialytic weight gain) were assessed. Hemodialysis was instituted at 28.7 ± 6.4 years of age. The primary cause of end‐stage renal disease was chronic glomerulonephritis in all of the patients except one, and in that patient it was polycystic kidney disease. As an index of the dialysis dose, sp. Kt/V was 1.2 ± 0.11. As an index of mineral metabolism, serum phosphate was 5.4 ± 0.9 mg/dL. As an index of anemia management, serum hemoglobin was 10.2 ± 1.2 g/dL. As indexes of nutrition, serum albumin was 4.0 ± 0.2 g/dL and interdialytic weight gain was 4.43 ± 1.36%. The sp. Kt/V‐value, serum phosphate, serum hemoglobin and interdialytic weight gain did not differ between the four different hemodialysis duration groups. Serum albumin was lower in the >30 group (4.0 ± 0.2 g/dL) than in the <10 group (4.2 ± 0.3 g/dL) (P = 0.046). As the duration of hemodialysis has increased, the age at hemodialysis induction has become younger. The cause of the renal failure was chronic glomerulonephritis in most of the cases. None had diabetic nephropathy. Improvement of the prognosis of patients with diabetic nephropathy is required. Most of the indexes of these patients nearly satisfied the recommended values.

Management of Osteoporosis in Chronic Kidney Disease

Chronic kidney disease (CKD) patients with coexisting osteoporosis are becoming common. Many of the therapeutic agents used to treat osteoporosis are known to be affected by the renal function. It is generally thought that osteoporosis in G1 to G3 CKD patients can be treated as in non-CKD patients with osteoporosis. In stage 4 or more advanced CKD patients and CKD patients on dialysis with osteoporosis, however, bisphosphonates must be used with caution, bearing in mind the potential development of such disorders as adynamic bone disease. The use of vitamin D preparations in low doses is relatively safe. In postmenopausal women, raloxifene must be administered with caution. When using denosumab, the serum calcium concentrations should be monitored carefully to prevent the development of hypocalcemia, and active vitamin D preparations should be administered concomitantly. The present article provides an overview of the management of osteoporosis in CKD patients.

Efficacy and Safety of Cinacalcet in Chronic Kidney Disease Stage III and IV

Treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) stage III and IV with vitamin D sterols is useful to maintain optimal parathyroid hormone (PTH) levels and thereby, reduces the severity of bone abnormalities caused by high PTH levels. However, it should be borne in mind that serum calcium (Ca) levels may easily increase as bone turnover is easily suppressed due to diffuse or early nodular parathyroid tissue in these patients. Furthermore, an elevated risk of cardiovascular disease due to advanced atherosclerosis associated with both secondary hyperparathyroidism and the administration of vitamin D sterols has been reported in patients with moderate to severe CKD, resulting in a high mortality in these patients. In order to control serum Ca levels, therefore, additional use of cinacalcet hydrochloride may be useful. However, acute reduction of serum Ca levels and chronic hyperphosphatemia should be avoided; therefore, the doses of phosphorus (P) binders should be increased or the initiation of low doses of vitamin D sterols may be favorable in patients with stage III and IV CKD receiving cinacalcet hydrochloride. The phosphaturic effect of FGF-23 after treatment with cinacalcet is estimated to be small as compared with that of vitamin D in moderate to severe CKD patients, therefore, evaluation of osteocytes should be performed in patients with secondary hyperparathyroidism treated with cinacalcet hydrochloride.