Undercarboxylated osteocalcin, the hypothalamic-pituitary-gonadal axis and glucose metabolism in male patients with osteoporosis.

Osteoporosis is a common disease that is characterized by low bone mass with
microarchitectural disruption and skeletal fragility, resulting in increased
risk of fracture. Normally, bone quality is maintained by a dynamic process,
known as bone remodeling.
Animal research shows that osteocalcin, secreted by osteoblasts, acts as a
hormone and influences the male gonal axis, insuline sensitivity and measures
of adiposity. However no study in humans to evaluate the relationship between
undercarboxylated osteocalcin, the gonadal axis and insulin sensitivity and
changes in body composition has been performed to date. Osteocalcin is not
available for administration in humans, but endogenous osteocalcin increases by
approximately 250% during daily administration of Teriparatide (rhPTH 1-34), an
anabolic agent used to treat osteporosis. Since PTH has no known effects on
insulin signalling and glucose homeostasis, we will administer Teriparatide to
study the effect of osteocalcin on insulin sensitivity, insulin secretion and
the HPG-axis in men with primary osteoporosis.

The objective of the study is to study the effect of Teripratide (rhPTH 1-34)
on undercarboxylated osteocalcin levels, testosterone concentrations, glucose
tolerance and insulin sensitivity and changes in body composition in male
subjects with primary osteoporosis.

Observational cohort study.

The participants will be randomized to two treatment groups, in a cross-over
design, with an one week wash-out period:
Group 1 will first receive subcutaneous Teriparatide 20*g daily (12 weeks) and
then no treatment
Group 2 will first receive no treatment (12 weeks) and then subcutaneous
Teriparatide 20*g daily (12 weeks)

During the intervention, participants will receive a subcutaneous injection
daily. This injection will only cause minor discomfort. The most common side
effect of Teriparatide treatment is leg cramps and pain (>10%). Other less
common side effects (1-10%) are dizziness, nausea, vomiting, gastroesophageal
reflux, chest pain, hypotension, headache, muscle weakness and depression.
Teriparatide is registered for the treatment of osteoporosis for a maximal
duration of 24 months, whereas our subjects will only use it for 12 weeks. When
the study ends all patients will continue with bisphosponate treatment. Both
anabolic and antiresorptive agents are approved for the treatment of
osteoporosis. But since it is only reimbursed in certain cases, Teriparatide is
not used as standard therapy for the treatment or prevention of osteoporosis.
After inclusion and subsequently every 6 weeks, fasting venous blood samples
will be drawn. At baseline and after 12 weeks of intervention (t=0 and t=12
weeks) patients will be admitted to the clinical research unit for two separate
days, for an oral glucose tolerance test (OGTT, 75 g oral glucose load) and a
hyperinsulinemic euglycemic clamp. The hyperinsulinemic euglycemic clamp will
be performed using stable isotopes. For the administration of the stable
isotope, glucose and insulin and for blood sampling, intravenous canules will
be inserted in an antecubital vein of each arm. Stable isotopes are not harmful
and hypoglycaemia will not occur because glucose is monitored every 5 minutes.
Total atmitting time on one day will not exceed 7 hours. The total volume of
blood samples from the entire protocol over 3 months will not exceed 475 ml
(blood samples 150 ml, OGTT 12 ml, hyperinsulinemic euglycemic clamp 320 ml).
At baseline and after 12 weeks of intervention patients will also have a
whole-body dual-energy X-ray absorptiometry (DXA scan) to measure body
composition. DXA radiation exposure poses a negligible risk.