Causes and Consequences of Adynamic Bone Disease

Little is known about the extent and severity of bone disease in children undergoing successful renal transplantation. To address this issue, 47 patients with stable renal function 3.2 +/- 1.7 years after transplantation (Tx) underwent iliac crest bone biopsy. The mean age of patients was 12 +/- 2.0 years; 36 had received cadaveric renal grafts, whereas 11 had undergone living-related Tx. Immunosuppressive drugs included cyclosporine 0.17 +/- 0.4 mg/kg/day, prednisone 7.5 +/- 2.1 mg/kg/day, and either azathioprine 1.6 +/- 0.9 mg/kg/day or mycophenolate mofetil 30 +/- 3 mg/kg/day. In addition to quantitative bone histomorphometry, the bone mineral content (BMC) of the lumbar spine was measured by dual energy X-ray absorptiometry (DXA) in 24/47 patients. Thirty-one transplant recipients had normal bone formation (N-Bfr), 11 had mild hyperparathyroidism (HPT) and 5 had adynamic skeletal lesions (AD). The interval since Tx, duration of dialysis before Tx and cumulative prednisone dose did not differ among groups. Trabecular bone area was highest in subjects with HPT. Unexpectedly, eroded bone perimeter exceeded normal reference values both in patients with AD and in those with N-Bfr; the osteoid area and osteoid perimeter were also elevated in these two groups. Hyperparathyroidism improved or resolved after Tx in all 14 subjects with this skeletal lesion prior to Tx, but one patient developed AD after Tx. Bone histology did not change after Tx in those with N-Bfr during regular dialysis, but bone formation increased after Tx in two of three patients with AD during regular dialysis. Z-scores for height in pre-pubertal patients after Tx were below age-appropriate values in each histologic subgroup, but values did not differ among groups. Z-scores for bone mineral content at the lumbar spine were also less than age-predicted values, -0.67 +/- 1.2. After adjusting for the degree of growth retardation, height-adjusted z-scores for lumbar spine BMC after Tx were above normal in all three histologic groups (0.68 +/- 1.0). The results suggest that reductions in bone mass and post-transplant osteoporosis are not prominent findings in pediatric renal transplant recipients when the influence of growth retardation on bone mass measurements by DXA is carefully considered.

Insulin-like growth factor-I (IGF-I) and -II are important local regulators of bone metabolism, but their role as determinants of human bone mass is still unclear. In the present study, we analyzed the concentration of IGF-I and -II in the bone matrix of 533 human biopsies from the iliac crest that were obtained during surgery for early breast cancer. There was an inverse association of bone matrix IGF-I concentration with age that was unaffected by menopause. Bone matrix IGF-I was positively associated with histomorphometric and biochemical parameters of bone formation and bone resorption and with cancellous bone volume. Based on the estimates of the linear regression analysis, women with a bone matrix IGF-I concentration 2 SD above the mean had a 20% higher bone volume than women with a bone matrix IGF-I concentration 2 SD below the mean. In contrast, serum IGF-I was neither correlated with bone turnover nor with bone volume and was only weakly associated with bone matrix IGF-I when adjusted for the serum concentration of IGF binding protein-3. Bone matrix IGF-II was positively associated with the osteoblast surface, but in contrast to IGF-I, tended to be positively associated with age and was unrelated to cancellous bone volume. In summary, our study suggests the following. 1) The concentration of IGF-I in cancellous bone undergoes age-related decreases that are similar to those of circulating IGF-I. 2) Menopause has no effect on this age-related decline. 3) Physiological differences in bone matrix IGF-I are associated with differences in iliac crest cancellous bone volume. 4) Bone matrix IGF-I is a better predictor of cancellous bone volume than circulating IGF-I. 5) The role of IGF-II in human bone tissue is clearly distinct from that of IGF-I.