Differential Effects of Growth Hormone and Alfa Calcidol on Trabecular and Cortical Bones in Hypophysectomized Rats

Growth hormone (GH) deficiency in children causes severe growth retardation, vitamin D deficiency, and osteopenia. We investigated whether alfacalcidol (1OHD) alone or in combination with GH can improve bone formation. Forty hypophysectomized female rats (HX) at the age of 8 wk were divided into HX, HX + 1OHD (oral 0.25 μg/kg daily), HX+GH (0.666 mg/0.2 mL SC daily) and HX+GH + 1OHD groups for a 4-wk study. Results showed that GH increased body weight, bone area, bone mineral content (BMC), and bone mineral density (BMD), whereas 1OHD only increased BMC and BMD. In cortical bone, GH increased both periosteal and endocortical bone formation resulting in a significant increase in cortical size and area in percentage, whereas 1OHD suppressed endocortical erosion surface per bone surface (ES/BS) without a significant effect on bone formation rate per bone surface (BFR/BS). In trabecular bone, GH mitigated the bone loss by increasing BFR/BS, whereas the 1OHD effect was by suppression of trabecular bone turnover in the HX rats. The combination of GH and 1OHD had no additive effect on increasing trabecular bone mass. In conclusion, GH activates new bone formation and increases bone turnover whereas 1OHD suppresses bone turnover. The combination intervention does not seem to provide any additive benefit.

[1]  J. Aloia,et al.  Synergistic Effect of Parathyroid Hormone and Growth Hormone on Trabecular and Cortical Bone Formation in Hypophysectomized Rats , 2010, Hormone Research in Paediatrics.

[2]  J. Adams,et al.  Back to the future: a new look at 'old' vitamin D. , 2008, The Journal of endocrinology.

[3]  W. Jee,et al.  Alfacalcidol-Stimulated Focal Bone Formation on the Cancellous Surface and Increased Bone Formation on the Periosteal Surface of the Lumbar Vertebrae of Adult Female Rats , 2008, Calcified Tissue International.

[4]  J. Iwamoto,et al.  Effects of alfacalcidol on cancellous and cortical bone mass in rats treated with glucocorticoid: a bone histomorphometry study. , 2007, Journal of nutritional science and vitaminology.

[5]  J. Iwamoto,et al.  Effect of risedronate on the cortical and cancellous bone mass and mechanical properties in ovariectomized rats: a comparison with the effects of alfacalcidol. , 2006, Journal of nutritional science and vitaminology.

[6]  J. Iwamoto,et al.  Comparative effects of alendronate and alfacalcidol on cancellous and cortical bone mass and bone mechanical properties in ovariectomized rats. , 2006, Experimental animals.

[7]  Alex J. Brown,et al.  The vitamin D prodrugs 1α(OH)D2, 1α(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells , 2006 .

[8]  J. Reginster,et al.  The therapeutic effects of alfacalcidol on bone strength, muscle metabolism and prevention of falls and fractures. , 2005, Journal of musculoskeletal & neuronal interactions.

[9]  B. Tönshoff,et al.  How safe is the treatment of uraemic children with recombinant human growth hormone? , 1991, Pediatric Nephrology.

[10]  P. Midgley Growth hormone therapy in children and adults , 2005 .

[11]  R. Erben,et al.  Vitamin D metabolites prevent vertebral osteopenia in ovariectomized rats , 1992, Calcified Tissue International.

[12]  D. Thompson,et al.  Alfacalcidol restores cancellous bone in ovariectomized rats. , 2003, Journal of musculoskeletal & neuronal interactions.

[13]  M. Bouxsein,et al.  Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization* , 2002, The Journal of Biological Chemistry.

[14]  W. Blum,et al.  Body composition, IGF-I and IGFBP-3 concentrations as outcome measures in severely GH-deficient (GHD) patients after childhood GH treatment: a comparison with adult onset GHD patients. , 2002, The Journal of clinical endocrinology and metabolism.

[15]  E. Ogata,et al.  Vitamin D Hormone Inhibits Osteoclastogenesis In Vivo by Decreasing the Pool of Osteoclast Precursors in Bone Marrow , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  H. Frost Growth Hormone and Osteoporosis: An Overview of Endocrinological and Pharmacological Insights from the Utah Paradigm of Skeletal Physiology , 2004, Hormone Research in Paediatrics.

[17]  S. Mohan,et al.  Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease. , 2000, The Journal of clinical endocrinology and metabolism.

[18]  L. Donahue,et al.  Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. , 2000, Endocrinology.

[19]  W. Daughaday Growth hormone axis overview – somatomedin hypothesis , 2000, Pediatric Nephrology.

[20]  E. Ogata,et al.  Alfacalcidol Inhibits Bone Resorption and Stimulates Formation in an Ovariectomized Rat Model of Osteoporosis: Distinct Actions from Estrogen , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  E. Ogata,et al.  The Advantage of Alfacalcidol Over Vitamin D in the Treatment of Osteoporosis , 1999, Calcified Tissue International.

[22]  E. Schacht,et al.  Rationale for Treatment of Involutional Osteoporosis in Women and for Prevention and Treatment of Corticosteroid-Induced Osteoporosis with Alfacalcidol , 1999, Calcified Tissue International.

[23]  J. Aloia,et al.  Effects of growth hormone and testosterone on cortical bone formation and bone density in aged orchiectomized rats. , 1999, Bone.

[24]  R. Erben,et al.  Therapeutic Efficacy of 1α,25-Dihydroxyvitamin D3 and Calcium in Osteopenic Ovariectomized Rats: Evidence for a Direct Anabolic Effect of 1α,25-Dihydroxyvitamin D3 on Bone1 , 1998 .

[25]  H. Burger,et al.  The Australian Multicenter Trial of Growth Hormone (GH) Treatment in GH-Deficient Adults. , 1998, The Journal of clinical endocrinology and metabolism.

[26]  J. Aloia,et al.  Histologic evidence: Growth hormone completely prevents reduction in cortical bone gain and partially prevents cancellous osteopenia in the tibia of hypophysectomized rats , 1997, The Anatomical record.

[27]  J. Aloia,et al.  Effects of estrogen and growth hormone on skeleton in the ovariectomized rat with hypophysectomy. , 1997, The American journal of physiology.

[28]  C. Higgins,et al.  Normalization of ion transport in murine cystic fibrosis nasal epithelium using gene transfer. , 1997, The American journal of physiology.

[29]  S. Wei,et al.  Growth hormone increases serum 1,25-dihydroxyvitamin D levels and decreases 24,25-dihydroxyvitamin D levels in children with growth hormone deficiency. , 1997, European journal of endocrinology.

[30]  A. Freemont,et al.  Demonstration of vitamin D receptor transcripts in actively resorbing osteoclasts in bone sections. , 1996, Bone.

[31]  R. Kumar,et al.  Ontogeny of the 1,25‐dihydroxyvitamin D3 receptor in fetal rat bone , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  R. Turner,et al.  Intermittent parathyroid hormone treatment increases osteoblast number, steady state messenger ribonucleic acid levels for osteocalcin, and bone formation in tibial metaphysis of hypophysectomized female rats. , 1995, Endocrinology.

[33]  W. Goodman,et al.  Growth hormone and calcitriol as modifiers of bone formation in renal osteodystrophy. , 1995, Kidney international.

[34]  J. Aloia,et al.  Skeletal alterations in hypophysectomized rats: I. A histomorphometric study on tibial cancellous bone , 1995, The Anatomical record.

[35]  J. Aloia,et al.  Skeletal alterations in hypophysectomized rats: II. A histomorphometric study on tibial cortical bone , 1995, The Anatomical record.

[36]  S. Mohan,et al.  Vitamin D deficiency causes a selective reduction in deposition of transforming growth factor beta in rat bone: possible mechanism for impaired osteoinduction. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Hock,et al.  Anabolic effect of human synthetic parathyroid hormone-(1-34) depends on growth hormone. , 1990, Endocrinology.

[38]  E. Ritz,et al.  1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. , 1989, Kidney international.

[39]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  R. Gray,et al.  Activation of renal 1,25-dihydroxyvitamin D3 synthesis by phosphate deprivation: evidence for a role for growth hormone. , 1985, Endocrinology.

[41]  L. Forte,et al.  Effects of hypophysectomy and growth hormone treatment on renal hydroxylation of 25-hydroxycholecalciferol in rats. , 1984, The Journal of endocrinology.

[42]  R. Tsang,et al.  Effects of growth hormone replacement therapy on 1,25-dihydroxyvitamin D and calcium metabolism. , 1983, The Journal of clinical endocrinology and metabolism.

[43]  C. Langman,et al.  25-hydroxyvitamin D3 (calcifediol) therapy of juvenile renal osteodystrophy: beneficial effect on linear growth velocity. , 1982, The Journal of pediatrics.

[44]  E. Spencer,et al.  The mechanism of the action of growth hormone on vitamin D metabolism in the rat. , 1981, Endocrinology.