Growth factors & osteoporosis

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0404019 & dopt=Abstract

J Bone Miner Res 1999 Jul;14(7):1182-8 Related Articles, Books, LinkOut

Oral administration of the growth hormone secretagogue MK-677 increases markers

of bone turnover in healthy and

functionally impaired elderly adults. The MK-677 Study Group.

MG, Bach MA, Plotkin D, Bolognese J, Ng J, Krupa D, Cerchio K, Gertz BJ.

Merck Research Laboratories, Rahway, New Jersey, USA.

Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover

and stimulates osteoblast activity when

given to elderly subjects. Probably a major effect of GH on bone is mediated

through stimulation of either circulating

or locally produced insulin-like growth factor I (IGF-I). We determined the

effect of chronic administration of the GH

secretagogue, MK-677, on serum IGF-I and markers of bone turnover in 187 elderly

adults (65 years or older) enrolled in

three randomized, double-blind, placebo-controlled clinical studies lasting 2-9

weeks. Urine was collected for

determination of N-telopeptide cross-links (NTXs), a marker of bone resorption,

and blood was collected for

determination of serum osteocalcin and bone-specific alkaline phosphatase

(BSAP), as bone formation markers, and serum

IGF-I levels pre- and post-treatment. Dose response data were initially obtained

in healthy elderly subjects who

received oral doses of 10 mg or 25 mg of MK-677 or placebo for 2 weeks (n =

10-12/group). Treatment with 10 mg and 25 mg

of MK-677 for 2 weeks increased mean urine NTXs 10% and 17%, respectively (p <

0.05 vs. placebo). Additionally, 50

healthy elderly subjects received either placebo (n = 20) for 4 weeks or 25 mg

of MK-677 (n = 30) daily for 2 weeks

followed by 50 mg daily for 2 weeks. MK-677 increased mean serum osteocalcin by

8% (p < 0.05 vs. placebo). In both

studies, MK-677 increased serum IGF-I levels significantly (55-94%).

Subsequently, the biological effects of MK-677 were

studied in 105 elderly subjects who met objective criteria for functional

impairment. Subjects were randomized to

receive oral doses of placebo for 9 weeks or either 5, 10, or 25 mg of MK-677

daily for an initial 2 weeks followed by

25 mg of MK-677 daily for the next 7 weeks(n = 63 on MK-677 and n = 28 on

placebo completed 9 weeks of therapy).

Treatment with MK-677 (all MK-677 groups combined) for 9 weeks increased mean

serum osteocalcin by 29.4% and BSAP by

10.4% (p < 0.001 vs. placebo) and mean urinary NTX excretion by 22.6% (p < 0.05

vs. placebo). The change from baseline

serum osteocalcin correlated with the change from baseline serum IGF-I in the

MK-677 group (r = 0.37; p < 0.01).

In conclusion, once daily dosing with MK-677, an orally active GH secretagogue,

stimulates bone turnover in elderly

subjects based on elevations in biochemical markers of bone resorption and

formation.

PMID: 10404019 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

0496146 & dopt=Abstract

J Pineal Res 1999 Sep;27(2):106-10 Related Articles, Books

Melatonin stimulates proliferation and type I collagen synthesis in human bone

cells in vitro.

Nakade O, Koyama H, Ariji H, Yajima A, Kaku T.

Department of Oral Pathology, School of Dentistry, Health Sciences University of

Hokkaido, Japan.

o-nakade@...

The pineal secretory product melatonin reportedly regulates release of growth

hormone in humans and prevents

phototherapy-induced hypocalcemia in newborn rats, suggesting that melatonin

affects bone metabolism. Little is known

about the effects of melatonin on bone in vitro or in vivo. The present study

was undertaken to examine whether

melatonin acts directly on normal human bone cells (HOB-M cells) and human

osteoblastic cell line (SV-HFO cells) to

affect osteogenic action in vitro. The effect of melatonin on bone cell

proliferation was determined using the

2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carbo xanilide (XTT)

assay after a 24 hr incubation with

melatonin. Melatonin significantly and dose-dependently increased the

proliferation in HOB-M cells and SV-HFO cells by

215 +/- 22.1%, and 193 +/- 6.4%), respectively, with a maximal effect at a

concentration of 50 microM. To evaluate the

effect of melatonin on bone cell differentiation, alkaline phosphatase (ALP)

activity, osteocalcin secretion and

procollagen type I c-peptide (PICP) production (a measure of type I collagen

synthesis) were measured after a 48 hr

treatment. While melatonin at micromolar concentrations did not significantly

affect either the ALP activity or the

osteocalcin secretion, it significantly and dose-dependently increased the PICP

production in HOB-M cells and SV-HFO

cells by 983 +/- 42.2%, and 139 +/- 4.2%, respectively, with the maximal

stimulatory doses between 50 and 100 microM.

These results provide new evidence that melatonin stimulates the proliferation

and type I collagen synthesis in human

bone cells in vitro, suggesting that melatonin may act to stimulate bone

formation.

PMID: 10496146 [PubMed - indexed for MEDLINE]

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701468 & dopt=Abstract

Bone 1998 Aug;23(2):103-9 Related Articles, Books

Arginine increases insulin-like growth factor-I production and collagen

synthesis in osteoblast-like cells.

Chevalley T, Rizzoli R, Manen D, Caverzasio J, Bonjour JP.

WHO Collaborating Center for Osteoporosis and Bone Diseases, Department of

Internal Medicine, University Hospital,

Geneva, Switzerland. chevalle@...

Protein-energy malnutrition, which is common in elderly patients with

osteoporotic hip fractures, is associated with

reduced plasma levels of insulin-like growth factor-I (IGF-I). IGF-I is an

important regulator of bone metabolism,

particularly of osteoblastic bone formation both in vivo and in vitro.

Pharmacological doses of arginine (Arg) increase

growth hormone (GH) and IGF-I serum levels. Whether amino acids, particularly

Arg, can directly modulate the production

of IGF-I by osteoblasts is not known. We investigated the effects of increasing

concentrations of Arg on IGF-I

expression and production, alpha1(I) collagen expression and collagen synthesis,

and cell proliferation and cell

differentiation, as assessed by alkaline phosphatase (ALP) activity and

osteocalcin (OC) release, in confluent mouse

osteoblast-like MC3T3-E1 cells. The addition of Arg (7.5-7500 micromol/L,

equivalent to 0.1- to 100-fold human plasma

concentration) for 48 h increased IGF-I production (adjusted for cell number) in

a concentration-dependent manner with a

maximum of 2.3 +/- 0.3-fold at 7500 micromol/L Arg [x +/- standard error of the

mean (SEM), n = 3 experiments, p <

0.01]. Arg (7.5-7500 micromol/L) increased the percentage of de novo collagen

synthesis in a concentration-dependent

manner (2.1 +/- 0.4-fold with 7500 micromol/L Arg, p < 0.001) and ALP activity

with a maximal stimulation of 144% +/-

13% plateauing at 750 micromol/l Arg (p = 0.002). The steady state level of

IGF-I messenger ribonucleic acid (mRNA) and

alpha1(I) collagen mRNA (both normalized to cyclophilin mRNA) of cells incubated

with Arg at high (100-fold) or low

(0.1-fold) human plasma concentrations, was 1.4 +/- 0.2, 1.2 +/- 0.2, and 1.1

+/- 0.2 after 24 h for the 7.5, 1.8, and

0.9 kb IGF-I mRNA transcripts, respectively (n = 3 experiments) and 1.5 +/- 0.2

and 3.1 +/- 0.7 after 24 and 48 h,

respectively, for the combined analysis of the 5.6 and 4.7 kb alpha1(I) collagen

mRNA transcripts (n = 3 experiments). A

maximal mitogenic effect (cell number) of +21% +/- 3% (p < 0.01) was obtained

with 1000 micromol/L Arg. In contrast, Arg

(7.5-7500 micromol/L) induced a reduction of OC production, which reached 30%

+/- 3% with 7500 micromol/L Arg (p =

0.02).

In conclusion, Arg stimulated IGF-I production and collagen synthesis in

osteoblast-like cells. Thus, Arg may influence

bone formation by enhancing local IGF-I production.

PMID: 9701468 [PubMed - indexed for MEDLINE]

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1063288 & dopt=Abstract

Rheumatol Int 2000;19(6):205-8 Related Articles, Books, LinkOut

Comparison of serum insulin-like growth factor-1 and growth hormone levels in

osteoporotic and non-osteoporotic

postmenopausal women.

Celiker R, Arslan S.

Hacettepe University School of Medicine, Department of Physical Medicine and

Rehabilitation, Ankara, Turkey.

celiker@...

The purpose of this study was to compare the insulin-like growth factor-1

(IGF-1) levels and the growth hormone (GH)

levels in osteoporotic and non-osteoporotic postmenopausal women. Eleven

non-osteoporotic postmenopausal women and 9

women with untreated postmenopausal osteoporosis were included in the study.

Bone mineral density (BMD) was assessed by

dual energy X-ray absorbtiometry. Serum was assayed for calcium, phosphorus,

alkaline phosphatase, bone-specific

alkaline phosphatase, parathyroid hormone, IGF-1 and GH levels. IGF-1 levels

were 98.8 +/- 43.5 ng/ml for osteoporotic

women and 169.8 +/- 50.3 ng/ml for the women with normal BMD (p < 0.05). GH

levels were 1.3 +/- 1.1 ng/ml and 1.3 +/-

1.0 ng/ml, respectively.

When compared with normal postmenopausal women, IGF-1 levels were found to be

lower in women with osteoporosis.

IGF-1 seems to play an important role in the development of low bone mass and

the present results suggest that IGF-1 is

a useful predictor of the presence of osteoporosis.

PMID: 11063288 [PubMed - indexed for MEDLINE]

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1204440 & dopt=Abstract

J Bone Miner Res 2001 Feb;16(2):398-405 Related Articles, Books, LinkOut

The influence of growth hormone deficiency, growth hormone replacement therapy,

and other aspects of hypopituitarism on

fracture rate and bone mineral density. .

Wuster C, Abs R, Bengtsson BA, Bennmarker H, Feldt-Rasmussen U, Hernberg-Stahl

E, Monson JP, Westberg B, Wilton P; The

KIMS Study Group and the KIMS International Board. Pharmacia & Upjohn

International Metabolic Database.

Department of Internal Medicine 1, Endocrinology and Metabolism, University

Medical Clinic, Heidelberg, Germany.

To assess the influence of factors affecting fracture risk and bone density in

adult hypopituitary patients with growth

hormone deficiency (GHD), data from a large-scale pharmacoepidemiological survey

(the Pharmacia & Upjohn International

Metabolic Database [KIMS]) were analyzed and compared with data from a control

population (the European Vertebral

Osteoporosis Study [EVOS]). The KIMS group consisted of 2084 patients (1112 men

and 972 women) with various types of

pituitary disease and EVOS consisted of 1176 individuals (581 men and 595

women). Fracture and bone mineral density

(BMD) data were available from 2024 patients from the KIMS group and 392

patients from EVOS. The prevalence of fractures

in patients with hypopituitarism was 2.66 times that in the non-GH-deficient

EVOS population. Adult-onset

hypopituitarism with GHD was associated with a higher fracture risk than

childhood-onset disease, and patients with

isolated GHD had a similar prevalence of fractures to those with multiple

pituitary hormone deficiencies. Hormonal

replacement therapy with L-thyroxine, glucocorticoids, and sex steroids did not

affect the risk of fracture in KIMS

patients. In addition, fracture rates in KIMS were independent of body mass

index (BMI) and the country of origin.

However, smoking was associated with a higher fracture rate in this group.

In summary, this is the first large-scale analysis to support the hypothesis of

an increased fracture risk in adult

patients with hypopituitarism and GHD.

This increased risk appears to be attributable to GHD alone, rather than to

other pituitary hormone deficiencies or to

their replacement therapy.

PMID: 11204440 [PubMed - indexed for MEDLINE]

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1146377 & dopt=Abstract

Horm Res 2000;54 Suppl 1:31-5 Related Articles, Books, LinkOut

Fracture rates in patients with growth hormone deficiency.

Wuster C.

Department of Internal Medicine 1, Endocrinology and Metabolism, University

Medical Clinic Heidelberg, Heidelberg,

Germany. chrw@...

There is some evidence that bone mass is reduced in the majority of adult

patients with growth hormone deficiency (GHD),

suggesting that such patients have an increased risk of fractures and clinically

significant osteoporosis. To date,

there have been only two reports of fracture rates in patients with

hypopituitarism. Both these retrospective studies

show an increased fracture prevalence in this patient group compared with the

general population, but patient numbers

were low for assessing fracture rates. However, an analysis of data from a

large-scale pharmacoepidemiological survey of

adults with GHD, KIMS (Pharmacia International Metabolic Database), confirms the

findings of these earlier studies. The

prevalence of all fractures among patients in KIMS was 2.7 times that in the

control population, and the risk of

fracture was independent of whether patients had isolated GHD or multiple

pituitary hormone deficiencies. The results

suggest that GHD is a risk factor for fractures, if a direct endocrine cause is

assumed.

Notably, there are some data on subgroup analyses from KIMS suggesting that

growth hormone replacement therapy may help

to reduce fracture risk, although further evidence is needed to confirm this

effect.

PMID: 11146377 [PubMed - indexed for MEDLINE]

========================

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0993598 & dopt=Abstract

Growth Horm IGF Res 1998 Feb;8 Suppl A:87-94 Related Articles, Books, LinkOut

Benefits of growth hormone treatment on bone metabolism, bone density and bone

strength in growth hormone deficiency and

osteoporosis.

Wuster C, Harle U, Rehn U, Muller C, Knauf K, Koppler D, Schwabe C, Ziegler R.

Department of Internal Medicine I-Endocrinology and Metabolism, University

Medical Clinic Heidelberg, Germany.

Bone mass is reduced in patients with GH deficiency (GHD) leading to an

increased vertebral fracture rate and clinically

significant osteoporosis. Patients with GHD of juvenile onset have reduced

skeletal mineralization. When substituting GH

in patients with GHD, bone turnover is increased and bone mineral density

initially decreases during the first year due

to the increase in remodelling space. From the experience in patients with

acromegaly, cortical bone mass is increased

and trabecular bone mass is normal in eugonadal or decreased in the hypogonadal

patients. However, bone mineral content

and bone area are increased leading to a higher biomechanical competence of bone

as shown in rats. In patients with GHD

of juvenile onset, mineralization and bone maturation are achieved during

treatment with GH in adult life after having

reached final body height leading to an increase in bone mass. The GH/ IGF-I

system is dysregulated in patients with

post-menopausal osteoporosis. This is shown by reduced systemic IGF and

IGFBP-3-levels in osteoporosis suggesting a

decrease of endogenous GH-secretion or a dysregulation of the GH receptor system

which is beyond the normal ageing

process of the GH/IGF system, the " somatopause " . A premature somatopause may be

responsible for the dysregulation in

some patients with osteoporosis. However, 24-h GH profiles do not differ between

patients suffering from osteoporosis or

osteoarthritis. Treatment of osteoporosis with GH might be beneficial due to the

increased bone metabolism and improved

bone geometry which occurs with GH.

The substantial increase of bone remodelling achieved with GH may be helpful

during late post-menopause with decreased

bone turnover and impaired osteoblastic function.

Using GH to prevent physiological bone loss that occurs with age seems possible,

but has to be discussed on an ethical

and economic basis.

PMID: 10993598 [PubMed - indexed for MEDLINE]

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Good Health & Long Life,

Greg ,

http://www.ozemail.com.au/~gowatson

gowatson@...