1) The document discusses several studies that examined the relationship between bone and fat mass. One study found lower levels of uncarboxylated osteocalcin in obese patients that normalized after gastric bypass surgery. 2) Another study found lower osteocalcin levels were associated with an increased risk of type 2 diabetes in men aged 60+. 3) A third study found osteocalcin was a negative predictor of fat mass and glucose levels in elderly men, but bone formation marker PINP was not an independent predictor. 4) Variation in the osteocalcin gene was also linked to body fat parameters in elderly women in one study discussed.

1. Montreal 2008Montreal 2008
Effects of bone on fatEffects of bone on fat
massmass
Highlights ASBMR, part 2Highlights ASBMR, part 2
Dr. E. van der VeerDr. E. van der Veer
University Medical Center GroningenUniversity Medical Center Groningen
Utrecht, Oct 8Utrecht, Oct 8THTH
20082008
ASBMRASBMR

2. ASBMR
Effects ofEffects of fat massfat mass onon bonebone
 Fat mass imposes mechanical stress on boneFat mass imposes mechanical stress on bone
 Adipocytes secretes biologically active moleculesAdipocytes secretes biologically active molecules
 EstrogenEstrogen
 ResistinResistin
 LeptinLeptin
 AdiponectinAdiponectin
 Interleukin – 6 (IL-6)Interleukin – 6 (IL-6)
 Pancreas secretes bone-active hormonesPancreas secretes bone-active hormones
 InsulinInsulin
 AmylinAmylin
 PreptinPreptin
 Adipocytes and osteoblasts have common progenitor,Adipocytes and osteoblasts have common progenitor,
the pluripotent mesenchymal stem cellthe pluripotent mesenchymal stem cell

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Osteoblasts andOsteoblasts and
adipocytes originateadipocytes originate
from commonfrom common
progenitor-progenitor-
mesenchymal stemmesenchymal stem
cellscells
Rosen et al 2006
Zhao et al 2008

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Effects ofEffects of bonebone onon fatfat massmass
Hormones that regulate fat/glucose metabolism have
effects on the skeleton,
But does bone regulate the energy homeostasis?
Mice with increased levels of uncarboxylated osteocalcin
(uOC) are protected from type 2 diabetes regulating
adiponectin secretion,
Mice lacking osteocalcin display decreased B-cell
proliferation, glucose intolerance and insulin resistance
(Lee NG et al, Cell 2007,130:458).

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Effects ofEffects of bonebone onon fat massfat mass
 SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity SpagnoliSpagnoli
Obese and Post Gastric By-pass patientsObese and Post Gastric By-pass patients
 SU 461SU 461 Osteocalcin and type II DiabetesOsteocalcin and type II Diabetes
NguyenNguyen
Men aged 60+
 SU 459SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
 SU 225SU 225 Osteocalcin gene andOsteocalcin gene and Body Fat MassBody Fat Mass McGuiganMcGuigan
Elderly Swedish WomenElderly Swedish Women
 SA 198SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern

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OsteocalcinOsteocalcin
Protein of 49 amino acidsProtein of 49 amino acids
3 glutamin residues3 glutamin residues
After carboxylation of theAfter carboxylation of the
GLU-residues binding to hydroxyapatiteGLU-residues binding to hydroxyapatite

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VITAMIN K CYCLEVITAMIN K CYCLE..
ORAL ANTICOAGULANTS INHIBIT THE
RECYCLING OF VITAMIN K
‘Inactive’
OSTEOCALCIN
OSTEOCALCIN

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Seeman et al. NEJM 2006
Bone turnoverBone turnover
PINP
BALP
Osteocalcine
CTx
Crosslinks
TRAP

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Effects ofEffects of bonebone onon fat massfat mass
 SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity SpagnoliSpagnoli
Obese and Post Gastric By-pass patientsObese and Post Gastric By-pass patients
 SU 461SU 461 Osteocalcin and type II DiabetesOsteocalcin and type II Diabetes
NguyenNguyen
Men aged 60+
 SU 459SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
 SU 225SU 225 Osteocalcin gene andOsteocalcin gene and Body Fat MassBody Fat Mass McGuiganMcGuigan
Elderly Swedish WomenElderly Swedish Women
 SA 198SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern

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Background:
In obese patients with diabetes, gastric bypass
surgery (GBS) through unknown mechanisms, leads
to ~90% resolution of type 2 diabetes before any
significant weight loss occurs.
SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli

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Study is designed to determine:
1) uOC levels in obese patients with and without diabetes
2) the effect of Gastric By-pass Surgery on uOC
3) the relationship of uOC with adiponectin and in turn with
insulin sensitivity.
SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli

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40 obese patients (BMI: 48.5±9.7 kg/m2)
- 19 had type 2 diabetes,
- 12 patients that had GBS 12-24 months prior to the study (post-GBS)
(BMI: 29±7 kg/m2);
- 16 normal weight age-matched control subjects (BMI: 25±3.3 kg/m2).
Measured:
glucose and insulin to determine HOMA, (Homeostatic model assessment
for quantifying insulin resistance)
serum total and uncarboxylated osteocalcin,
serum HMW-adiponectin by RIA or IRMA.
SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli

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SA 444SA 444
Osteocalcin andOsteocalcin and
ObesityObesity
SpagnoliSpagnoli

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Inverse correlation was found between:
uOC and HMW-adiponectin r = -0.28 p=0.02
uOC and HOMA r = -0.33 p=0.006
HMW-adiponectin and HOMA r = -0.32 p=0.008
Conclusion
In obese patients uOC levels are decreased, and normalize post-GBS.
These data support the hypothesis that uOC is a bone hormone that
regulates insulin sensitivity by modulating adiponectin.
Spagnoli et al postulate that normalization of uOC is a mechanism for
diabetes resolution post-GBS.
SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli

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Effects ofEffects of bonebone onon fat massfat mass
 SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
 SU 461 Osteocalcin and type II Diabetes
Nguyen
Men aged 60+
 SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
 SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
 SU 225 Osteocalcin gene and Body Fat Mass McGuigan
Elderly Women

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SU 461 Osteocalcin and type II Diabetes
Nguyen
Background:
 Serum osteocalcin (OC), a 49-amino acid bone matrix protein, has
recently been shown to be associated with diabetes in mice.
 However, it is unknown whether the association is present in men.
Aim:
 Therefore, this study sought to examine the contribution of OC to the
susceptibility of type II diabetes in men

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Serum OC, sex hormone binding globulin (SHBG), 25(OH)D, and PTH were
measured by radioimmunoassay in 443 men aged 60+ at baseline (1989) in the
Dubbo Osteoporosis Epidemiology Study.
The men’s health status, including fracture and diabetes, had been monitored
between 1989 and 2007. Bone mineral density (BMD), clinical risk factors, and
lifestyle factors had also been obtained at baseline and subsequent biannual visits.

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SU 461 Osteocalcin and type II Diabetes
Nguyen
Conclusion
 Osteocalcin and serum testosteron were independent
risk factors for type II diabetes
 Thus, these data suggest that lower osteocalcin were
associated with an increased risk of type II diabetes in
men.
 The use of serum OC may help improve the prognostic
accuracy of type II diabetes in men.

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Effects ofEffects of bonebone onon fat massfat mass
 SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
 SU 461 Osteocalcin and type II Diabetes
Nguyen
 SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
 SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
 SU 225 Osteocalcin gene and Body Fat Mass McGuigan
Elderly Women

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Background:
 Osteocalcin affect adiposity and glucose homeostasis in
mice, suggesting that the skeleton via an endocrine
mechanism influences energy metabolism.
Aim:
 To investigate the relationship between plasma
osteocalcin and parameters reflecting fat mass and
glucose homeostasis in humans.
SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom

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SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
Methods:Methods:
1010 elderly men (75.3± 3.2 years) of the MrOS Sweden study,1010 elderly men (75.3± 3.2 years) of the MrOS Sweden study,
non-diabetic n= 857non-diabetic n= 857
diabetic n= 153.diabetic n= 153.
 Fasting levels were analysed ofFasting levels were analysed of
plasma osteocalcin,plasma osteocalcin,
plasma glucose,plasma glucose,
serum insulin andserum insulin and
lipidslipids
 Fat mass and lean mass were analysed using dual energy X-rayFat mass and lean mass were analysed using dual energy X-ray
absorptiometry.absorptiometry.

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SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
BMI
Total
body fat
Glucose
(fasting)

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Pearson’s correlation coefficients for
associations with Osteocalcin
ASBMR

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SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
ASBMR

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SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
 PINPPINP is strongly associated withis strongly associated with OsteocalcinOsteocalcin
Pearson’s r = 0.66Pearson’s r = 0.66
 Both bone formation markers were included together asBoth bone formation markers were included together as
covariates in linear regression models:covariates in linear regression models:
OC was independently predicting glucose and fat mass,OC was independently predicting glucose and fat mass,
but PINP not.but PINP not.
ASBMR

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SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
Conclusion:Conclusion:
 Osteocalcin is a negative predictor of fat mass andOsteocalcin is a negative predictor of fat mass and
plasma glucose in elderly menplasma glucose in elderly men
 In contrast, PINP is not an independent predictorIn contrast, PINP is not an independent predictor
 These human data support recently publishedThese human data support recently published
experimental studies, revealing endocrine functions ofexperimental studies, revealing endocrine functions of
osteoblast-derived osteocalcin on glucose and fatosteoblast-derived osteocalcin on glucose and fat
homeostasis.homeostasis.

30. ASBMR
Effects ofEffects of bonebone onon fat massfat mass
 SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
 SU 461 Osteocalcin and type II Diabetes
Nguyen
 SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
 SU 225 Osteocalcin gene and Body Fat Mass McGuigan
Elderly Swedish Women
 SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern

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SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
Aim:
 To determine the relationship between variation in the
osteocalcin gene with bone density, fracture and body fat
parameters
Methods:
 1044 elderly women all 75 years old at baseline
Follow-up 9 years

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SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
4 SNPs around Osteocalcin locus on Chr 1,
including rs1800247 located in the promoter
rs 2842880 in intron 13
rs 933489 in intron 14

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SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
• Osteocalcin SNP’s were associated with % total body fat at baseline
rs1800247 located in the promoter (p=0.045)
rs 2842880 in intron 13 (p=0.009)
• No longer significant after correction for height
Changes in body fat between baseline and 5 years follow-up
The heterozygotes appeared to loose the most fat mass.

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SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
Conclusion:
 The variation in the osteocalcin gene is linked both to
BMD and to fracture in elderly Caucasian women
 Interestingly, we can not exclude an independent
influence of the variation in the osteocalcin gene on
changes in fat mass

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Effects ofEffects of bonebone onon fat massfat mass
 SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
 SU 461 Osteocalcin and type II Diabetes
Nguyen
 SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
 SU 225 Osteocalcin gene and Body Fat Mass McGuigan
Elderly Swedish Women
 SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
Elderly

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SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
Aim:
To investigate the relationship between
osteocalcin and indicators of the metabolic syndrome
Methods:
619 randomly selected 70 years old men and women
longitudinal study with examinations at age 70, 76 och 86

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Results
• Osteocalcin increased by 44 percent from 70 to 86 years of age.
This increase was related to, but independent of,
declining kidney function (cystatin C)
increasing PTH.
• Inverse correlation was found between:
OC and BMD
OC and BMI
in both sexes at all ages investigated (P<0.05).
OC adjusted for BMI:
OC and insulin r = -0.11 p<0.01
OC and glucose r = -0.25 p<0.0001
A multiple regression model (diabetes excluded) with osteocalcin as
dependent variable showed that glucose, (but not insulin), waist circumference
and BMD were independent indirect predictors
While PTH, cystatin C and ALP were independent direct predictors of
osteocalcin (p <0.001).
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern

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OC was inversely related to the risk of having bilateral carotoid plaques
(OR per SD increase in osteocalcin 0.68 (95% CI 0.47 - 0.97)).
The risk for stroke within 15 years after the age of 70 was increased in men
with low serum osteocalcin (p<0.01).
Low osteocalcin increased the risk of having high waist circumference (
Men > 102 cm, women > 88 cm;
OR per SD increase in osteocalcin 0.77 (0.67-0.89).
Low osteocalcin predicted the parameters of the metabolic syndrome
high waist circumference, (p<0.01)
BMI >30,
high triglycerides,
hypertension
diabetes.
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern

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Conclusion:
Low serum osteocalcin predicts high glucose and carotid
plaques and indicators of the metabolic syndrome.
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern

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bone regulates the
energy homeostasis
ASBMR 2008
osteocalcin

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Central Regulation of BoneCentral Regulation of Bone
RemodelingRemodeling
interaction between bone and braininteraction between bone and brain
Rosen
2008
Cell Metab
Baldock et
al 2007
Lundberg et
al 2007
Sato et al 2007
Lee et al 2007

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Met dank aan de Nederlandse collegae voor de leerzame discussies tijdens
de ASBMR

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 Diabetic subjects had lower plasma osteocalcin (-21.7 %, p< 0.001)Diabetic subjects had lower plasma osteocalcin (-21.7 %, p< 0.001)
than non-diabetic subjects.than non-diabetic subjects.
 For both all subjects and non-diabetic subjects, plasma osteocalcinFor both all subjects and non-diabetic subjects, plasma osteocalcin
was clearly inversely related to BMI, fat mass and plasma glucosewas clearly inversely related to BMI, fat mass and plasma glucose
(p< 0.001), while it was not associated with height or lean mass.(p< 0.001), while it was not associated with height or lean mass.
 Plasma osteocalcin explained a substantial part (6.3%) of thePlasma osteocalcin explained a substantial part (6.3%) of the
variance in plasma glucose while it associated moderately withvariance in plasma glucose while it associated moderately with
serum insulin.serum insulin.
 Multiple linear regression models adjusting for serum insulin and fatMultiple linear regression models adjusting for serum insulin and fat
mass demonstrated that plasma osteocalcin was an independentmass demonstrated that plasma osteocalcin was an independent
negative predictor of plasma glucose (p< 0.001).negative predictor of plasma glucose (p< 0.001).

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Methods and population
619 randomly selected 70 years old men and women
longitudinal study with examinations at age 70, 76 och 86.
BMD was measured in calcaneus with dual photon absorptiometry and
osteocalcin was analysed by a double-antibody radioimmuno-assay.
Serum was sampled after 10 hours fasting and non-smoking in the morning.
Extra- and intracranial circulation was examined by means of duplex sonography and
Transcranial Doppler techniques in 142 subjects at age 78.