GH Therapy Cuts Number With Osteopenia in Half in GH-Deficient Adults

Abstract

Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults.

To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover.
BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxy-terminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment.
The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P<0. 001), 5.9% (P<0.01) in the femoral neck, 4.9% (NS, P>0.05) in the Ward’s triangle and 8.2% (P<0.001) in the trochanter area. The serum concentrations of PICP (202.6+/-11.5 vs 116.3+/-5.4 microg/l; mean+/-s.e.m.) and ICTP (10.5+/-0.6 vs 4.4+/-0.3 microg/l) doubled (P<0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0+/-10.4 and 5.6+/-0.7 microg/l respectively), despite constantly elevated serum IGF-I levels (39. 6+/-4.1 nmol/l at 42 months vs 11.9+/-0.9 nmol/l at baseline; P<0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P<0.001 for all; ANOVA) and of the BMD in the lumbar spine (P<0.05), in the femoral neck and the trochanter (P<0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P<0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P<0.05) in those with normal bone status (P<0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P<0. 05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD.
GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.

Välimäki MJ, Salmela PI, Salmi J, Viikari J…
Eur. J. Endocrinol. Jun 1999
PMID: 10377504 | Free Full Text

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Moreover, in more than a half of the patients the criteria of osteopenia disappeared or there was an improvement of the bone state from osteoporosis to osteopenia.

GH Therapy for 1 Year Increases Bone Turnover and Density in GH Deficiency

Abstract

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up.

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward’s triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.

Finkenstedt G, Gasser RW, Höfle G, Watfah C…
Eur. J. Endocrinol. Mar 1997
PMID: 9100553

GH for 36 vs. 6-12 Months

Abstract

Long-term change in the bone mineral density of adults with adult onset growth hormone (GH) deficiency in response to short or long-term GH replacement therapy.

Only two previous studies have assessed the effects of long-term GH replacement therapy on bone mineral density (BMD) in patients with adult onset GH deficiency. To date no study has looked at the long-term impact on BMD after a short course (6-12 months) of GH replacement. In two groups of patients with adult onset GH deficiency we have studied BMD either (a) after 3 years of continuous GH replacement or (b) 2 years after completion of a short course of GH.
An open GH therapeutic study in which patients were recruited from a previous double-blind placebo-controlled study. The BMD status of all patients was unknown to the physician and patient at the time of recruitment.
Group A (n = 7, three females) all received GH replacement continuously for 3 years. Group B (n = 8, five females) included six patients who received GH replacement for 6 months and two who received GH replacement for 12 months with BMD being measured at 6-monthly intervals.
Single photon absorptiometry (SPA) and later single X-ray absorptiometry (SXA) were used to measure forearm cortical BMD. Dual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine, trochanteric, femoral neck and Ward’s area BMD.
In group A lumbar spine and trochanter BMD had increased significantly from baseline by 3.7% (DXA: median change = 0.045 g/cm2; P = 0.028) and 4.0% (DXA: median change = 0.031 g/cm2; P = 0.046), respectively. There were non-significant decreases in femoral neck (1.9%) (DXA: median change = -0.02 g/cm2; P = 0.39), Ward’s area (6.5%) (DXA: median change = -0.06 g/cm2; P = 0.09) and forearm (2.6%) (SPA/SXA: median change = -0.013 g/cm2; P = 0.18). In group B, compared with baseline, only trochanter BMD changed significantly, increasing by 5.9% (DXA: median change = 0.0485 g/cm2; P = 0.049). Lumbar spine (DXA: median change = -0.001 g/cm2) Ward’s area (DXA: median change = 0.0135 g/cm2), femoral neck (DXA: median change = -0.005 g/cm2) and forearm cortical (SPA/SXA; median change = -0.01 g/cm2) BMD did not change significantly (P = 0.67, P = 0.57, P = 0.86 and P = 0.31, respectively). Median percentage changes compared with baseline were -0.1%, 1.8%, -0.5% and -2.1%, respectively. From the time of completion of GH therapy however, BMD increased significantly at lumbar spine, (median change = 0.023 g/cm2), Ward’s area (median change = 0.03 g/cm2) and trochanter (median change = 0.056 g/cm2) (P = 0.036, P = 0.049 and P = 0.012, respectively) but not at the femoral neck (median change = 0.017 g/cm2; P = 0.31) or forearm (median change = 0 g/cm2; P = 0.75).
Long-term GH replacement therapy for three years appears to have beneficial effects on bone in patients with adult onset GH deficiency particularly at the lumbar spine and trochanter; the effects on femoral neck and forearm cortical BMD, however, are less impressive. A short course (6-12 months) of GH replacement therapy results in an increase in trochanter BMD several years later, and after an initial decline in BMD whilst on GH replacement, lumbar spine and Ward’s area BMD return towards their baseline values. These results emphasize that not all types of bone and skeletal sites respond to GH therapy identically. Furthermore a short course of GH replacement over 6-12 months may result in significant changes in BMD several years later.

Rahim A, Holmes SJ, Adams JE, Shalet SM
Clin. Endocrinol. (Oxf) Apr 1998
PMID: 9640413

GH Improves Bone in GH Deficiency – 4 Year Study

Abstract

Effect of long-term treatment with GH on bone metabolism, bone mineral density and bone elasticity in GH-deficient adults.

Adults with GH deficiency (GHD) commonly have subnormal bone mineral density (BMD), and have been reported to have an increased risk of fractures. It has been suggested that GH replacement therapy may have beneficial effects on bone in such patients. The aim of this study was to investigate the effects of long-term GH replacement therapy on bone metabolism, BMD and bone elasticity in adults with GHD.
At the start of the study, 20 adults with GHD were randomized to receive either GH, 0.25 IU/kg/week (the ‘GH group’) or placebo (the ‘placebo group’). After 6 months, patients in the placebo group were switched to GH therapy, and all patients received GH for a further 42 months.
Of the 20 patients included in the study, 11 were male and nine were female. Mean age at the start of the study was 42.5 +/- 10.1 years. All patients had been GH-deficient for at least 2 years before the start of the study.
Rates of bone resorption and formation were assessed by measuring serum levels of type I collagen carboxyterminal cross-linked telopeptide (ICTP) and carboxyterminal propeptide of type I procollagen (PICP), respectively. BMD was measured at the lumbar spine by dual-photon absorptiometry (DPA) and at the non-dominant forearm by single-photon absorptiometry (SPA). Bone elasticity was assessed by measuring apparent phalangeal ultrasound transmission velocity (APU).
The main results in the GH group were as follows. The rate of bone resorption increased significantly during the first 6 months of treatment and remained significantly elevated above its baseline level thereafter. The rate of bone formation also rose during the first 6 months of treatment and remained elevated thereafter, but was significantly higher than at baseline only after 24 months of treatment. At both sites measured, BMD was subnormal at baseline, decreased during the first 6 months of treatment, and increased progressively for the rest of the study, eventually rising well above its baseline level. Bone elasticity decreased during the first 6 months of treatment, but had returned to its baseline level after 24 months.
Our results support previous findings that BMD is subnormal in adults with GHD, that GH replacement therapy can stimulate bone turnover in such adults and that, in the long term, such stimulation results in a significant increase in BMD. In addition they show, for the first time, that BMD may continue to rise even after GH replacement therapy has been administered for 4 years, and indicate that bone elasticity is not adversely affected by long-term GH therapy.

Kann P, Piepkorn B, Schehler B, Andreas J…
Clin. Endocrinol. (Oxf) May 1998
PMID: 9666867

Xylitol Improves Bone Strength, Elasticity, and Volume in Rats

Abstract

Improved bone biomechanical properties in rats after oral xylitol administration.

The effects of 5, 10, and 20% dietary xylitol supplementations on the biomechanical properties, histological architecture, and the contents of collagen, pyridinoline, and deoxypyridinoline in long bones of rats were studied. Tibiae were used for the three-point bending test, and femurs were used for the torsion and loading test of the femoral neck. The 10 and 20% oral xylitol administrations caused a significant increase of tibial stress, femoral shear stress, and stress of the femoral neck as compared with the controls. Parallel, but not significant, effects were also seen in the 5% xylitol supplementation group. No significant differences in strain or Young’s modulus of the tibiae were detected between the groups. An increased shear modulus of elasticity in femurs was detected in the 20% supplementation group as compared with the controls. The histomorphometrical data for the secondary spongiosa of the proximal tibia revealed that trabecular bone volume was significantly greater in all dietary xylitol supplementation groups as compared with the controls. The bone volume increased along with increasing xylitol content. No significant differences between the groups were detected concerning the amount of collagen per dry weight of organic matrix, the concentrations of pyridinoline or deoxypyridinoline in collagen, or the ratio of these crosslinks. This suggests no xylitol-dependent selective changes in these structures of bone collagen. In conclusion, dietary xylitol supplementation in rats improves the biomechanical properties of bone and increases the trabecular bone volume dose dependently.

Mattila P, Knuuttila M, Kovanen V, Svanberg M
Calcif. Tissue Int. Apr 1999
PMID: 10089228

Xylitol Improves Bone Strength in Rats

Abstract

Improved bone biomechanical properties in xylitol-fed aged rats.

Our previous studies have shown that dietary xylitol protects against weakening of bone biomechanical properties in experimental postmenopausal osteoporosis. To study whether xylitol preserves bone biomechanics also during aging, a long-term experimental study was performed with rats. Twenty-four male Sprague-Dawley rats were divided into 2 groups. The rats in the control group (NON-XYL group) were fed a basal rat and mouse no. 1 maintenance (RM1) diet, while the rats in the experimental group (XYL group) were continuously fed the same diet supplemented with 10% xylitol (wt/wt). The rats were killed after 20 months. Their femurs were prepared for biomechanical analyses and scanning analyses with peripheral quantitative computed tomography (pQCT). In 3-point bending of the femoral diaphysis, maximum load, maximum elastic load, stiffness, energy absorption, elastic energy absorption, ultimate stress, and yield stress were significantly greater in the XYL group than in the NON-XYL group. This indicates a xylitol-induced improvement of both structural and material strength properties of cortical bone. Accordingly, the maximum load of femoral neck was significantly greater in the XYL group. In the pQCT analysis of femoral diaphysis, cortical bone area, cortical thickness (CtTh) periosteal circumference, and cross-sectional moment of inertia were greater in the XYL group. The endosteal circumference was smaller in the XYL group. In the pQCT analysis of the femoral neck cortical area of the midneck was significantly greater in the XYL group. This data indicates that xylitol exerted beneficial effects on the cross-sectional architecture of the bones. In conclusion, continuous moderate dietary xylitol supplementation leads to improved bone biomechanical properties in aged rats concerning both bone structural and material strength properties.

Mattila PT, Svanberg MJ, Jämsä T, Knuuttila ML
Metab. Clin. Exp. Jan 2002
PMID: 11782878

Xylitol + Alcohol > Xylitol Alone For Bone Resorption and Density in Rats

Abstract

The effect of a simultaneous dietary administration of xylitol and ethanol on bone resorption.

Our previous studies have shown that dietary xylitol supplementation diminishes bone resorption in rats, as well as protects against ovariectomy-induced increase of bone resorption during experimental osteoporosis. Interestingly, ethanol, when given simultaneously with xylitol, is known to increase blood concentration of xylitol. On the other hand, ethanol, when given alone, has been shown to increase bone resorption. The aim of the present study was to evaluate the effects of a simultaneous dietary administration of 10% xylitol and 10% ethanol on bone resorption. Bone resorption was determined using measurement of urinary excretion of hydrogen 3 (3H) radioactivity in 3H-tetracycline prelabeled rats. Already 4 days after the beginning of dietary supplementations, excretion of 3H was about 15% lower in the xylitol group (diet supplemented with 10% xylitol) and about 25% lower in the xylitol-ethanol group (diet supplemented with 10% xylitol and 10% ethanol) as compared to the controls. The excretion of 3H in these groups remained smaller than that of the controls throughout the entire study period of 40 days. The excretion of 3 H in the xylitol-ethanol group remained also smaller than that of the xylitol group. Bone mineral density and bone mineral content were determined with a peripheral quantitative computed tomography (pQCT) system from the rat tibiae at the end of the experiment. Trabecular bone mineral density and trabecular bone mineral content were significantly greater in the xylitol group and in the xylitol-ethanol group compared to the controls. They were also greater in the xylitol-ethanol group as compared to the xylitol group. Cortical bone mineral density and cortical bone mineral content did not differ significantly between the groups. In conclusion, a simultaneous dietary supplementation with 10% xylitol and 10% ethanol seems to diminish bone resorption and to increase trabecular bone mineral density and trabecular bone mineral content in rats. These effects seem to be stronger than the effects induced by 10% xylitol supplementation alone.

Mattila PT, Kangasmaa H, Knuuttila ML
Metab. Clin. Exp. Apr 2005
PMID: 15798965

Xylitol Protects Bone in Arthritic Rats

Abstract

Dietary xylitol protects against the imbalance in bone metabolism during the early phase of collagen type II-induced arthritis in dark agouti rats.

The aim of the present study was to evaluate the changes in bone metabolism during the early phase of type II collagen-induced arthritis in rats and to evaluate whether a 10% dietary xylitol supplementation is able to protect against these changes. Arthritis was induced in female dark agouti rats by injections of type II homologous rat collagen emulsified with an equal volume of incomplete Freund adjuvant. In one group, the diet was supplemented with 10% xylitol. After 17 days, the rats were killed. Serum osteocalcin, as a marker of bone formation, and serum tartrate-resistant acid phosphatase, as a marker of bone resorption, were measured. Histologic measurements were made from Masson-Goldner trichrome-stained sections of distal tibiae. All the collagen-injected rats had arthritic symptoms at the end of the experiment. Serum osteocalcin was significantly higher in the collagen-injected rats fed a xylitol-supplemented diet (CI-X) than in the collagen-injected rats not fed xylitol (CI) and in the controls. Serum tartrate-resistant acid phosphatase was significantly higher in the CI and CI-X groups than in the controls. Trabecular bone volume was significantly lower in the CI group as compared with the CI-X and control groups. These results suggest that, at the time of the appearance of arthritic symptoms, bone resorption activity is high, but bone formation is not severely affected. Furthermore, dietary xylitol seems to protect against the imbalance of bone metabolism during the early phase of collagen type II-induced arthritis.

Kaivosoja SM, Mattila PT, Knuuttila ML
Metab. Clin. Exp. Aug 2008
PMID: 18640381

Xylitol Increases Bone Density in Rat Femur

Abstract

The effects of oral xylitol administration on bone density in rat femur.

To examine the effects of oral xylitol administration on rat femur bone density, 36 four-week-old male Wistar rats divided into three groups were fed CE-2 diet (control, n = 12) alone or supplemented with 10% (n = 12) or 20% (n = 12) dietary xylitol for 40 days. Biochemical, morphological, and histological analyses were performed. The 10% and 20% xylitol groups showed higher levels of both serum Ca and alkaline phosphatase activity and lower levels of serum tartrate-resistant acid phosphatase than the control group. Although no significant differences in the three-dimensional bone structure or trabecular bone structure of the femur were observed, both xylitol groups showed significantly higher bone density than the control group. Compared to the control group, the 10% and 20% xylitol groups showed an increase in trabeculae. Thus, oral administration of xylitol appears to affect bone metabolism, leading to increased bone density in rat femur.

Sato H, Ide Y, Nasu M, Numabe Y
Odontology Jan 2011
PMID: 21271323

Xylitol Preserves Bone in Ovariectomized Rats

Abstract

Dietary xylitol protects against weakening of bone biomechanical properties in ovariectomized rats.

The effects of dietary xylitol (xyl) on bone biomechanical properties in ovariectomized rats (ovx) were studied. Forty-two 3-mo-old female Wistar rats were divided into three groups of 14. Rats in two groups were ovariectomized, while those in the control group underwent a sham operation. All rats received a basal diet, and half of the ovx were given an additional 10 g/100 g dietary xyl supplementation. Three months later the rats were killed and their tibias, femurs and humeri were prepared. The tibias were used for analyses of bone density and trabecular bone volume (BV/TV) and for the three-point bending test. The femurs were used for the torsion test and for the loading test of the femoral neck. The humeri were used for analyses of bone ash weight and bone concentrations of calcium and phosphorus. Dietary xyl gave a significant protection against ovariectomy-caused decline of tibial stress in the three-point bending test, of femoral shear stress in the torsion test, and of stress of the femoral neck, without affecting bone elasticity values. Xyl restricted the ovariectomy-caused reduction in bone density, in bone ash weight and in concentrations of bone calcium and phosphorus. Furthermore, trabecular bone loss in ovx was significantly suppressed by dietary xyl. These results indicate that a 10% dietary supplementation of xyl in ovx has a protective effect against the weakening of bone biomechanical properties. This is related to greater BV/TV and maintained bone mineral content.

Mattila PT, Svanberg MJ, Pökkä P, Knuuttila ML
J. Nutr. Oct 1998
PMID: 9772154 | Free Full Text