Logistics/management problems at the recruiting center

This is an interventional study on nutraceuticals. It is a randomized controlled, open-label, prospective, single-center study that involves the enrollment of 82 patients with osteoporosis and 41 subjects without osteoporosis.

The hypothesis the decarboxylated form of Osteocalcin (OC), called GluOC, represents a clinically useful marker for monitoring the effects of supplementation with vitamin K in association with anabolic treatment with teriparatide will be analyzed not only on bone but also on skeletal muscle and energy metabolism in patients with severe osteoporosis.

Background:

OC, also known as bone-Gla-protein (BGP), is the main non-collagen protein of the extracellular matrix in mineralized tissues. It is synthesized by osteoblasts, odontoblasts, and hypertrophic chondrocytes and, through its negative charges, binds calcium and regulates the formation of hydroxyapatite crystals.

In humans, circulating OC levels negatively correlate with fasting blood glucose and insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), body mass index (BMI), hyperlipidemia, and circulating concentrations of leptin. Weight loss (resulting from diet and / or physical activity) improves metabolic profile and muscle strength and increases OC levels.

It's interesting to note that high plasma levels of vitamin K or dietary supplementation (MK-7, the natural derivative of vitamin K2), correlate with a reduction in the loss of bone mass and quality. In addition, short-term (1 week) and long-term (3 years) vitamin K supplementation improves insulin resistance in both young and old males and high vitamin K consumption is associated with reduced insulin resistance and reduced risk of developing type 2 mellitus diabetes.

Recently, it has been reported in mice that the combination of teriparatide (TPT) and vitamin K is more effective than ionotherapy in improving bone formation, bone density and strength, and in inhibiting bone resorption.

Given the putative relevance of the decarboxylated form of OC, GluOC, in the endocrine interaction between bone and organs responsible for the management of energy resources (e.g. endocrine pancreas, skeletal muscle and adipose tissue) whose function is deregulated in elderly subjects and in the syndrome of fragility, this study aims to define a role of supplementation with vitamin K in osteoporosis, another condition characterizing the frailty of the elderly, on the endocrine function of bone tissue and the consequent effects on energy metabolism.

There is various evidence regarding the usefulness of using the decarboxylated form of OC as a biomarker for monitoring the response to anti-osteoporotic treatments. In particular, the circulating levels of GluOC respond both to osteometabolic treatments (teriparatide) and to supplementation with vitamin K, in a more relevant way than to total osteocalcin.

Study design and treatment:

The study includes the following phases:

1. enrollment of controls, after obtaining informed consent.
2. enrollment of patients, after obtaining informed consent.
3. randomization for the patient group
4. prescription teriparatide +/- Vitamin K depending on the group to which it belongs
5. re-evaluation of patients after 6, 12 and 18 months of treatment

The group of patients randomized to the teriparatide + Vitamin K / Menaquinone MK-7 arm will have to take MK-7 at a dose of 375 microg / day.

Randomization:

Patients with osteoporosis will be randomized 1: 1 to one of two treatment groups:

• Teriparatide + Vitamin K
• Teriparatide

The randomization list will be generated with SAS 9.4 software (SAS Institute Inc., Cary, USA) and foresees the presence of blocks.

Statistical Analysis:

The analysis of the covariance will be performed to evaluate the effect of treatment with and without vitamin K / MK-7 on the primary endpoint measured at 18 months, adjusting for its baseline value (α = 0.05, two-tailed test). The results will also be described in terms of means and 95% confidence intervals both of the absolute values of GluOC at 18 months and of its variations from baseline. This approach will also be followed for the evaluation of the effect of the intake of vitamin K / MK-7 on the secondary endpoints defined by the OC isoforms.

The association between GluOC and Gla-type Osteocalcin (GlaOC) levels at 18 months (and changes from baseline) with respect to the markers of energy, bone and muscle metabolism measured at 18 months will also be explored through a linear regression model.

Inclusion Criteria

Inclusion criteria for the group "Patients with osteoporosis":

• Age ≥ 65 years
• Serum levels of 25OHD> 30 ng / ml (as per clinical practice)
• Adequate calcium intake (assessed by questionnaire)
• Diagnosis of severe primary osteoporosis
• Criteria for the prescription and reimbursement of treatment with Teriparatide 20 microg / day subcutaneous according to the Italian Agency of Pharma (AIFA) 79
• Patient suitable for treatment with MK-7
• Informed consent freely acquired before the person was enrolled

Inclusion criteria for the group "subjects without osteoporosis":

• Age ≥ 65 years
• Serum levels of 25OHD> 30 ng / ml (as per clinical practice)
• Adequate calcium intake (assessed by questionnaire).
• Informed consent freely acquired before the person was enrolled

Exclusion Criteria:

Exclusion criteria for the group of "Patients with osteoporosis":

• causes of secondary osteoporosis: current glucocorticoid therapy, active and uncontrolled rheumatic diseases, endogenous hypercortisolism, uncontrolled hyperthyroidism or hypothyroidism (except known hypothyroidism well compensated with L-thyroxine), chronic renal failure (IRC) with glomerular filtration rate (GFR) <30 ml / min, multiple myeloma, liver failure (chronic liver disease of CHILD class B and C), heart failure (New York Heart Association, also said NHYA) NHYA> 2, active neoplasms, type 1 and type 2 diabetes mellitus
• ongoing therapies: glucocorticoids, antiepileptics, aromatase inhibitors and similar gonadotropin-releasing hormone (GnRH, contraindicated for teriparatide).

Exclusion criteria for the group "subjects without osteoporosis":

• ongoing therapies: glucocorticoids, antiepileptics, diphosphonates, teriparatide, denosumab, statins, oral or injective hypoglycemic agents, aromatase inhibitors, similar GnRH or other oncological therapies
• diagnosis of osteoporosis (according to World Health Organization, WHO) T-score <-2.5 standard deviation (SD), at any site evaluated with ''Dual-Energy X-ray Absorptiometry'' (DXA)
• diagnosis of sarcopenia (according to ''Appendicular Skeletal Muscle Mass'', ASMMI) ASMMI <7.59 kg / m2 for males and 5.47 kg / m2 for females evaluated with DXA
• diagnosis of IRC with estimated GFR <30 ml / minute, liver failure (chronic liver disease of CHILD class B and C), heart failure with NHYA> 2 , active neoplasms, endocrinopathies (except known hypothyroidism well compensated with L-thyroxine ), type 1 and type 2 diabetes mellitus.