Background

Idiopathic adynamic bone disease (ABD) in dialysis patients is characterized by low serum parathyroid hormone (PTH) concentration. Whether ABD itself causes serious disease is controversial. Fuller understanding of both primary hypoparathyroidism and secondary hypoparathyroidism resulting in a long-standing low-PTH state may shed light on properties of ABD.

Methods

We performed histomorphometric analysis in bone specimens from biopsy in two female patients with primary hypoparathyroidism and in an autopsy specimen of bone from a male patient with secondary hypoparathyroidism related to long-term hemodialysis; respective ages, 45, 58, and 65 years; dialysis duration, 6 years, 2 months, and 30 years; lumbar bone mineral density, 2.88, 2.43, and 4.1 SD above the normal mean; and serum intact PTH, <5, <20, and <84 pg/mL (mean, 30.4). Tetracycline labeling was performed in the first two cases.

Results

Histomorphometric analysis in the first two cases indicated a diagnosis of ABD, since no tetracycline labeling could be seen along most of trabecular bone surfaces, total osteoid volume was decreased, and fibrous tissue was minimal. Bone volume was preserved, and the dense bone-trabecular connectivity was noted, with normal lamellar structure. A small number of hump-like structures protruded from the quiescent surface of trabecular bone, a pattern which has been called "minimodeling." Tetracycline label was observed in only a small area within trabecular bone in patient 1, and at a region of trabecular bone surface showing minimodeling in patient 2.

The third case was also diagnosed as ABD; cancellous lamellar structure and bone volume were normal, although trabecular connectivity was poor and island bone was relatively prominent. Minimodeling was evident. Minimodeling bone volume/total bone volume in these three cases was 9.0%, 13.1%, and 6.8%, respectively; number of minimodeling sites/total bone volume (N/mm²) was 4.9, 8.6, and 9.0, respectively.

Conclusion

Bone formation mechanism by minimodeling might contribute to preserving bone volume in dialysis patients with hypoparathyroidism, even in the absence of remodeling stimulated by PTH.

CASE PRESENTATIONS

Case 1

A 45-year-old Japanese woman was admitted to our institution on July 26, 1998, for the evaluation of low serum PTH. In May 1990, she manifested renal dysfunction, as well as hypocalcemia leading to convulsions. The serum creatinine concentration was 7.3 mg/dL; serum calcium, 2.7 mEq/L; phosphate, 6.2 mg/dL; and intact parathyroid hormone (i-PTH), less than 5.0 pg/mL. This patient's renal diagnosis was unclear since renal biopsy was not performed. However, Alport syndrome or chronic glomerulonephritis was suspected because of proteinuria (2 g/day), hematuria(6 to 10 cells per high power field (HPF), and sensorineural deafness. The patient was treated with 0.5 g of vitamin D₃ derivatives and 3 g of calcium carbonate daily to prevent hypocalcemia, and symptoms remitted. In 1992, hemodialysis three times a week was initiated and was continued at an outpatient clinic. Since initiation of dialysis, serum i-PTH remained less than 5 pg/mL; serum calcium, 4.5 to 5.0 mEq/L; serum phosphate, 5.0 to 7.0 mg/dL; and osteocalcin, 10 to 13 mg/mL. No bone pain and no fractures were noted during follow-up.

On admission, the patient was 157 cm in height, and her postdialysis "dry" weight was 54.9 kg. Her blood pressure was 110/68 mm Hg. She had bilateral cataracts, hypertelorism, brachydactyly of the fifth digits, and sensorineural deafness. The serum concentrations of urea nitrogen were 56 mg/dL; creatinine, 10.0 mg/dL; alkaline phosphatase, 98 IU/L; calcium, 5.0 mEq/L; phosphate, 5.6 mg/dL; aluminum, 20 and 25 g/L (before and after deferoxamine at a dose of 5 mg/kg); iron, 76 g/dL; unsaturated iron binding capacity (UIBC), 137 g/dL; ferritin, 29 g/L; and magnesium, 1.7 mEq/L. The serum concentration of PTH was less than 5.0 pg/mL and osteocalcin was 11.6 ng/mL. Computed tomography of the brain showed small bilateral putaminal calcifications. The patient was diagnosed with primary hypoparathyroidism, given the absence of other manifestations of endocrinopathy, acquired causative factors such as surgery, radioiodine therapy, or infection, or any family history.

Bone radiographs showed a sclerotic pattern and revealed no fracture lines. The patient's BMD was measured by dual-energy x-ray absorptiometry (DEXA). Lumbar spine (L3) BMD was 2.88 SD above the mean peak normal bone mass (T score), and BMD in the unshunted forearm was 0.93 SD over the corresponding normal mean (T score). BMD measurements repeated for 11 years (1990 to 2001) have not changed. On July 28, 1998, a right iliac bone biopsy was performed, 14 days after administration of tetracycline for triple-labeling studies.

Case 2

A 58-year-old Japanese woman was admitted to our institution on November 1, 1999, for evaluation of low serum PTH. In 1989, when cerebral infarction occurred, she was diagnosed with diabetes mellitus. Her mother and her younger brother were known to have diabetes. In 1996, her renal dysfunction was detected during evaluation of an upper respiratory infection. The serum creatinine concentration was 12.5 mg/dL; serum calcium, 3.1 mEq/L; phosphate, 5.2 mg/dL; and i-PTH, 19.3 pg/mL. The original renal diagnosis in this patient was unclear since no kidney biopsy had been obtained. However, diabetic nephropathy was suspected because of proteinuria (2.4 g/day) in the absence of hematuria. The patient was treated with 1 to 2 g of calcium carbonate daily to prevent hypocalcemia. Although the patient's renal function showed gradual worsening, i-PTH remained less than 20 pg/mL. In September 1999, hemodialysis was begun three times a week.

On admission, the patient was 148 cm in height and her dry weight was 47.5 kg. Her blood pressure was 140/82 mm Hg. She had bilateral diabetic retinopathy. Serum urea nitrogen was 71 mg/dL; creatinine, 7.6 mg/dL; alkaline phosphatase, 175 IU/L; calcium, 4.4 mEq/L; phosphate, 6.9 mg/dL; aluminum, 16 and 18 g/L (before and after deferoxamine at a dose of 5 mg/kg); iron, 41 g/dL; UIBC, 177 g/dL; ferritin, 44 g/L; and magnesium, 1.5 mEq/L. Serum PTH was 1.3 pg/mL and osteocalcin was 9.9 ng/mL. Computed tomography of the brain showed small bilateral putaminal calcifications. The patient was diagnosed with primary hypoparathyroidism in addition to diabetes mellitus because she showed no any known causes or family history related to primary hypoparathyroidism.

Bone radiography showed a sclerotic pattern and revealed no fracture lines. BMD of the lumbar spine at L3 was 2.43 SD above the normal mean (T score), and BMD in the unshunted forearm was 1.24 SD over the normal mean (T score). BMD has not decreased during a follow-up period of 5 years (1996 to 2001). Bone pain and fractures have not occurred. On November 4, 1999, right iliac bone biopsy was performed, 14 days after administration of tetracycline for double-labeling studies.

Case 3

A 65-year-old Japanese man died from asphyxiation associated with acute bronchitis in March 2001. Hemodialysis twice a week had been initiated in 1971 because of chronic renal failure due to gouty nephropathy. To prevent secondary hyperparathyroidism, the patient was treated continuously with 0.5 to 1.0 g of vitamin D₃ derivatives daily, beginning in 1978. Orally administered aluminum gels were replaced by 3 to 4 g of calcium carbonate daily given as a phosphate binder beginning in 1987. In 1987, amyloid nodules containing ₂-microglobulin were resected bilaterally from the ishial tuberosities. Bilateral carpal tunnel syndrome and destructive spondyloarthropathy of the cervical spine (C4 to C7) were diagnosed. No pathologic fractures were noted during 30 years of follow-up. Since initiation of dialysis, serum PTH (measured as the middle fragment and the carboxy-terminal fragment by radioimmunoassay) remained low at 2.2 to 4.3 ng/mL and 2.2 to 8.4 ng/mL; since 1990, i-PTH measured by immunoradiometric assay (IRMA) showed a low concentration of 30.4 22.5 pg/mL (mean SD; range,12 to 83); Calcium was 4.6 0.3 mEq/L and phosphate was 5.5 1.2 mg/dL, during the preceding 11 years.

On admission, the patient was 165 cm in height and his dry weight was 47.7 kg. Laboratory results about 1 month before autopsy were serum urea nitrogen, 44 mg/dL; creatinine, 6.6 mg/dL; alkaline phosphatase, 223 IU/L; calcium, 4.4 mEq/L; phosphate, 6.6 mg/dL; aluminum, 10 and 12 g/L (before and after deferoxamine at a dose of 5 mg/kg); iron, 38 g/dL; UIBC, 198 g/dL; ferritin, 65 g/L; and magnesium, 1.7 mEq/L. Serum i-PTH was 44.3 pg/mL and osteocalcin was 10.7 ng/mL. BMD of the lumbar spine at L3 was 4.1 SD above the normal mean (T score), and BMD in the unshunted forearm was 1.8 SD above the normal mean (T score). BMD showed no decrease during a follow-up period of 6 years (1994 to 2000). Since the right iliac bone specimen was obtained at autopsy, tetracycline for double-labeling analysis had not been administered.

Bone biopsy specimens

Undecalcified thin sections 5 mm in thickness prepared from bone specimens were stained by the Villanueva methods. Sections were observed with an epifluorescence microscope, using ultraviolet excitation. With a portion of bone trabecula magnified at 160, parameters were directly measured with an image-analysis system linked to a microcomputer. Histomorphometric findings are indicated in Table 1 (case 1 and case 2) and Table 2 (case 3).

Table 1 - Histomorphometric analysis of the bone.

Full table

Table 2 - Histomorphometric analysis of the bone.

Full table

Light microscopic examination showed low normal bone volume in case 1, and markedly increased bone volume in case 2, in comparison with age- and gender-matched controls Figure 1 a and b. Dense bone-trabecular connectivity was evident. Numbers of osteoblasts and osteoclasts both were decreased, as was the amount of osteoid. Very little fibrous tissues were present. Polarizing microscopy indicated normal lamellar cancellous bone Figure 2 a and b. However, a small number of hump-like structures protruded from the quiescent surface of trabecular bone, a pattern which has been called "minimodeling " Figure 3 a and b. In case 1 and case 2, ratios of minimodeling bone volume to total bone volume were 9.0% and 13.1%, respectively; ratios of number of minimodeling sites to total bone volume (N/mm²) were 4.9 and 8.6, respectively. Fluorescence microscopy did not show labeling by tetracycline at most trabecular bone surfaces. Focally, tetracycline labeling was observed in only a small area within trabecular bone in case 1 Figure 4a and in a region of minimodeling of the trabecular bone surface in case 2 Figure 4b. No staining for aluminum was evident. Histomorphometric analysis according to previous criteria^7,8 yielded a diagnosis of aplastic or adynamic bone disease, with decreased total osteoid volume (<15%), essentially no fibrous tissue volume (<0.5%), and a decreased bone formation rate.

Figure 1.

Light microscopic examination of the two cases showed normal bone volume in case 1 (A), and markedly increased bone volume in case 2 (B). Light microscopic examination of case 3 (C) also showed normal bone volume in comparison with age- and gender-matched controls. However, bone trabecular connectivity was poor, and island bone was rather prominent. (A) Villanueva staining, original magnification 40; (B) original magnification 40; (C) original magnification 40.

Full figure and legend (180K)

Figure 2.

Polarizing microscopy indicated normal lamellar cancellous bone in case 1 (A) and case 2 (B), and case 3 (C) showed that most of the cancellous bone had lamellar structure, while woven bone was visible only in small areas. (A), (B), and (C) original magnification 40.

Full figure and legend (192K)

Figure 3.

A small number of hump-like structures (arrows) protrude from the quiescent surface of trabecular bone, a pattern which has been called "minimodeling" in case 1 (A) and case 2 (B). Hump-like bone formations (arrows) representing minimodeling sites were evident in case 3 (C, D). (A) Villanueva staining 100; (B) Villanueva staining 200; (C) Villanueva staining 100; (D) polarizing microscopy 100.

Full figure and legend (95K)

Figure 4.

Fluorescence microscopy did not show labeling by tetracycline at most trabecular bone surfaces. Focally, tetracycline labeling was observed in only a small area (white arrows) within trabecular bone in case 1 (A) (magnification 100), and in a region of minimodeling (white arrows) of the trabecular bone surface in case 2 (B) (magnification 200).

Full figure and legend (86K)

Light microscopic examination of case 3 also showed normal bone volume in comparison with age- and gender-matched controls. However, bone trabecular connectivity was poor, and island bone was rather prominent Figure 1c. Polarizing microscopy showed that most of the cancellous bone had lamellar structure, while woven bone was visible only in small areas Figure 2c. Total osteoid volume was small (<15%), fibrous tissue was very scant (<0.5%), eroded surface was decreased, and numbers of osteoblasts and osteoclasts both were decreased. Adynamic bone was diagnosed according to previous criteria^7,8, without measurement of bone formation rate by tetracycline labeling. No aluminum staining was seen. As in case 1 and 2, hump-like bone formations representing minimodeling sites were evident Figure 3 c and d. The ratio of minimodeling bone volume to total bone volume in this patient was 6.8%; the ratio of number of minimodeling sites to total bone volume (N/mm²) was 9.04.

DISCUSSION

Various bone lesions occurring in patients with chronic renal failure share the general name of "renal osteodystrophy" (ROD). Osteodystrophy is divided into osteitis fibrosa (high-turnover bone), osteomalacia (low-turnover bone), a mixed type with features of both osteitis fibrosa and osteomalacia, and a "mild" type. Osteitis fibrosa resulting from excessive PTH and osteomalacia resulting from aluminum deposition have been of major clinical importance. ABD represents an additional type of low-turnover bone disease characterized clinically by a low serum PTH concentration, and histologically by low bone turnover, absence of fibrous tissue, and a normal amount of osteoid. ABD is distinct from the mild type of ROD because of the decreased bone formation rate in ABD. Initially, ABD was reported to be associated with aluminum deposition as well as musculoskeletal manifestations such as bone pain, proximal myopathy, and pathologic fractures. After aluminum phosphate-binding preparations were replaced by CaCO₃ and a reverse-osmotic apparatus was adopted for processing water for dialysate, exposure to aluminum has been minimized^9,10,11. Idiopathic ABD subsequently has emerged as distinct from ABD secondary to aluminum exposure. The idiopathic form has been reported to be more prevalent in patients undergoing CAPD, elderly persons, and diabetic patients⁴. Like aluminum-related ABD, idiopathic ABD was considered to carry clinical risks; a low PTH concentration could be associated with increased likelihood of fractures, and a plasma i-PTH concentration of 100 to 300 pg/mL was believed necessary for normal bone homeostasis in uremic state.

Atsumi et al¹ reported that among 187 male hemodialysis patients, those with serum PTH concentrations in the lowest tertile (5 to 60 pg/mL) had a risk of vertebral fracture 2.4 times greater than for the middle tertile (62 to 202 pg/mL). Patients with low serum PTH therefore were considered susceptible to vertebral fracture because of decreased lumbar spine BMD. Coco and Rush² found the incidence of hip fracture between 1988 and 1998 in 1272 dialysis patients to be increased in individuals with low serum i-PTH levels (<65 pg/mL).

Meanwhile, Niikura et al⁵ reported that both at initiation of hemodialysis and 6 years later, BMD measured in the lumbar spine using single-photon absorptiometry did not differ between a group with relative hypoparathyroidism and an other group matched for age, gender, and dialysis duration but without any hypoparathyroidism. Abdelhadi and Nordenstrom⁶ assessed BMD overall and in the distal radius, femoral neck, and lumbar spine by DEXA in 20 patients treated surgically for hyperparathyroidism associated with hemodialysis. BMD was measured before parathyroidectomy and 1, 2, and 3 years afterward. After parathyroidectomy, BMD showed a marked increase amounting to 7% to 23% at all sites. These authors concluded that although PTH concentrations that had been lowered by parathyroidectomy remained persistently low, BMD did not show a decrease. Considering these various studies, whether ABD itself causes fractures and/or reduced BMD remains controversial.

However, these reports, in which BMD was evaluated during a limited period of 3 to 6 years, included no truly long-term study of patients with sustained low PTH. Because patients with primary hypoparathyroidism have had low circulating PTH levels for a long time, often from birth, characterizing the bone lesion in this disease could shed considerable light on ABD. Several studies of bone parameters in hypoparathyroidism have shown greater BMD than in age- and gender-matched controls¹², but histomorphometric analysis of the bone has not yet been reported to our knowledge.

According to histomorphometric analysis of bone in our two patients with primary hypoparathyroidism, cancellous trabecular bone showed findings of ABD, including a paucity of tetracycline labeling (decreased bone formation rate), a decrease in both osteoblast and osteoclasts, scant osteoid, and no fibrous tissue. However, mineralized bone was shown to abundant by both histomorphologic analysis and by BMD measurement using DEXA. Since evidence of the minimodeling phenomenon was present in our two cases and tetracycline labeling occurred in an area with minimodeling, bone formation by this mechanism might be responsible for preserving bone volume despite hypoparathyroidism and a very slow bone formation rate.

Next, to elucidate whether this minimodeling mechanism was limited to primary hypoparathyroidism, or also would be applicable also to patients with true ABD developing following induction of dialysis, we performed bone histomorphometric analysis in an autopsy case (case 3) with hemodialysis duration of 30 years; his serum PTH concentration had remained low over a long period. Although this case was different from the first two in that bone trabecular connectivity was poor, island bone was prominent, and woven bone was visible in only small areas; adynamic bone still could be diagnosed according to previous criteria^7,8. Bone volume was preserved by both histomorphologic analysis and BMD measurement using DEXA. Like cases 1 and 2, hump-like bone formations indicating minimodeling were evident.

Formation of cancellous bone may occur according to both remodeling and minimodeling mechanisms. In remodeling, bone formation by osteoblasts occurs only where bone resorption by osteoclasts has previously occurred¹³. Remodeling is regulated systemically by PTH, 1,25-dihydroxyvitamin D, and other hormones. In minimodeling, bone formation resulting from osteoid deposition and successive mineralization occurs at a quiescent bone surface without prior bone resorption by osteoclasts. Newly formed bone, therefore, protrudes from older bone. In this process, osteoblasts and osteoclasts work separately. Linear dividing lines between newly formed bone and old bone can be observed as "lamellar separation." Minimodeling is reported to be regulated by dynamic external stress according to Wolff's law^14,15,16,17. Among patients in an ABD state because of low PTH, bone volume of immobilized individuals with extremely limited exercise would be lost because minimodeling would not be stimulated. However, bone volume could be preserved in otherwise similar patients with exercise sufficient to stimulate minimodeling.

Although several reports have concluded that idiopathic ABD does not cause symptoms, other authors report that the disease is associated with an increased fracture rate¹³. Our study and others suggest that ABD patients with high bone volume may be asymptomatic, but bone pain or bone fractures may be expected in ABD patients with osteopenia. An additional problem experienced by patients with ABD is a relatively high incidence of hypercalcemia. Consequences could include ectopic calcification in vascular walls, since low bone turnover is associated with decreased ability of the skeleton to take up calcium. Therefore, careful management of calcium-phosphorus balance using calcium carbonate and vitamin D₃ derivatives is needed in patients with ABD.

Plasma intact PTH levels, determined with the IRMA assay for intact PTH (Nicols Institute Diagnostics, San Juan Capistrano, CA, USA), have been considered as equal to 1-84 fragments of PTH and have provided a valuable means for measuring current PTH secretion levels. However, some cases have been found in which i-PTH, using this assay, do not correspond with histologic low-turnover bone levels¹⁸. The lack in the utility of this i-PTH as a bone marker has been recognized, and its use has become no longer helpful as an indicator of bone turnover. Recently, IRMA assay has indicated, not only the ability to measure the intact molecule of 1-84 PTH, but also to measure other less biologically active PTH fragments^{19,20,21,22,23}. PTH 1-84 and total PTH have been measured by means of a more sensitive assay provided by Scantibodies Laboratory, Inc. (Santee, CA, USA). This assay's PTH 1-84 is considered to be more precise than intact PTH. PTH 7-84, calculated by the difference between total PTH and PTH 1-84 levels, has been postulated as being a possible factor of bone resistance. Monier-Faugere et al²⁴ considered the possibility that PTH 7-84 probably consists of amino terminally truncated PTH fragments (C-PTH fragments), and the PTH 1-84/C-PTH fragment ratio was thus predicted as a potential parameter of low bone turnover. However, Coen et al²⁵ have proposed a contrary result, in that this rationale does not discriminate among the three histologic groups (low-turnover bone, hyperparathyroidism, and mixed osteodystrophy). Although PTH 1-84 may be a good index, an accurate interpretation of PTH 7-84 will necessitate further examination.

CONCLUSION

We performed histomorphometric analysis in bone specimens from patients in long-standing low-PTH states including both primary hypoparathyroidism and secondary hypoparathyroidism related to long-term hemodialysis. Although ABD was diagnosed in all three patients, bone volume was preserved with normal lamellar structure. Minimodeling was present in the all three cases. Bone formation by minimodeling may be responsible for preservation of bone volume in patients with ABD. In the future, investigation of minimodeling may help to clarify bone formation mechanism of various forms of ROD, including ABD.

References

REFERENCES

1. Atsumi, K, Kushida, K, Yanazaki, K, et al: Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis 1999 33: 287–293,  | Article | PubMed | ISI | ChemPort |
2. Coco, M, Rush, H: Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 2000 36: 1115–1121,  | Article | PubMed | ISI | ChemPort |
3. Pirano, B, Chen, T, Cooperstein, L, et al: Fracture and vertebral bone mineral density in patients with renal osteodystrophy. Clin Nephrol 1988. 30: 57–62,  | PubMed | ISI | ChemPort |
4. Hercz, G, Pei, Y, Greenwood, C, et al: Aplastic osteodydtrophy without aluminum: The role of " suppressed"parathyroid function. Kidney Int 1993 44: 860–866,  | Article | PubMed | ISI | ChemPort |
5. Nikura, K, Akizawa, T, Satoh, Y, et al: Relative hypoparathyroidism in hemodialysis patients. Miner Electrolyte Metab 1995 21: 101–103,  | PubMed |
6. Abderhadi, M, Nordenstrom, J: Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 1998 83: 3845–3851,  | Article | PubMed | ISI | ChemPort |
7. Sherrard, DJ, Baylink, DJ, Wergedal, JE, et al: Quantitative histological studies on the pathogenesis of uremic bone disease. J Clin Endo Metab 1974 39: 119–135,  | ISI | ChemPort |
8. Sherrard, DJ, Ott, SM, Maloney, NA, et al: Uremic osteodystrophy: Classification, cause, and treatment, in Clinical Disorders of Bone and Mineral Metabolism, 1983, edited by Frame B, Potts JT Jr., Amsterdam, Excerpta Media, pp 254–259
9. Sherrard, DI, Hercz, G, Pei, Y, et al: The spectrum of bone disease in end-stage renal failure-an evolving disorder. Kidney Int 1993 43: 436–442,  | Article | PubMed | ISI | ChemPort |
10. Couttenye, MM, D'haese, PC, Broe, ME: What considerations should we give to adynamic bone disease. J Artificial 1998 21: 687–692,  | ChemPort |
11. Ubara, Y: Bone histomorphometrical analysis in patients on long-term dialysis treatment for more than 10 years. Osaka City Med J 1998 44: 133–13,  | PubMed | ChemPort |
12. Fitzpatrick, LA, Arnpld, A: Hypoparathyroidism, in Endocrinology (3rd ed.), 1995 edited by DeGroot LJ, Philadelphia, W.B. Saunders,
13. Hruska, KA, Teitelbaum, SL: Renal osteodystrophy. N Eng J Med 1995 333: 166–174,  | ISI | ChemPort |
14. Frost, HM: Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff's Law: The bone modeling problem. Anat Rec 1990 226: 403–413,  | Article | PubMed | ISI | ChemPort |
15. Frost, HM: Skeletal structural adaptations to mechanical usage (SATMU): 2. Redefining Wolff's Law: The remodeling problem. Anat Rec 1990 226: 414–422,  | Article | PubMed | ISI | ChemPort |
16. Frost, HM: Skeletal structural adaptations to mechanical usage (SATMU): 3.The hyaline cartilage modeling problem. Anat Rec 1990 226: 423–432,  | Article | PubMed | ISI | ChemPort |
17. Frost, HM: Skeletal structural adaptations to mechanical usage (SATMU): 4. Mechanical influences on intact fibrous tissues. Anat Rec 1990 226: 433–439,  | Article | PubMed | ISI | ChemPort |
18. Malluche, HH, Monier-Faugere, MC: Understanding and managing hyperphosphatemia in patients with chronic renal disease. Clin Nephrol 1999 52: 267–277,  | PubMed | ISI | ChemPort |
19. Brossaro, JH, Cloutier, M, Roy, L, et al: Accumulation of a non-(1–84) molecular form of parathyroid hormone(PTH) detected by intact PTH assay in renal failure: Importance in the interpretation of PTH values. J Clin Endocrinol Metab 1996 81: 3923–3929,  | Article | PubMed | ISI | ChemPort |
20. Lepage, R, Roy, L, Brossaro, JH, et al: A non-(1–84) corculating parathyroid hormone(PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998 44: 805–809,  | PubMed | ISI | ChemPort |
21. John, MR, Goodman, WG, Gao, P, et al: A novel immunoradiometric assay detects full-length human PTH but not amino-terminally truncated fragments: Implications for PTH measurements in renal failure. J Clin Endocrinol Metab 1999 84: 4287–4290,  | Article | PubMed | ISI | ChemPort |
22. Slatopolsky, E, Finch, J, Clay, P, et al: A novel mechanism for skeletal resistance in uremia. Kidney Int 2000 58: 753–761,  | Article | PubMed | ISI | ChemPort |
23. Gao, P, Scheibel, S, D'Amour, P, et al: Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1–84: Implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res 2001 16: 605–614,  | Article | PubMed | ISI | ChemPort |
24. Monier-Faugere, MC, Geng, Z, Mawad, H, et al: Improved assessment of bone turnover by the PTH-(1–84)/large C-PTH fragment ratio in ESRD patients. Kidney Int 2001 60: 1460–1468,  | Article | PubMed | ISI | ChemPort |
25. Coen, G, Bonucci, E, Ballanti, P, et al: PTH "1–84" and PTH 7–84 in the noninvasive diagnosis of renal bone disease. Am J Kidney Dis 2002 40: 348–354,  | Article | PubMed | ISI | ChemPort |

Acknowledgments

Histomorphometric analysis of bone was performed by Dr. Hideaki Takahashi and Mrs. Akemi Itou at the Niigata Bone Science Institute, Japan. The author thanks members of "Bone Clubs," including Yoshindo Kawaguchi for kind advice throughout the course of this study.