Tier 2 — strong

Alpha-Ketoglutarate Decreases Serum Levels of C-terminal Cross-Linking Telopeptide of Type I Collagen (CTX) in Postmenopausal Women with Osteopenia: Six-Month Study

Filip RS, Pierzynowski SG, Lindegard B, Wernerman J, Haratym-Maj A, Podgurniak M

International Journal for Vitamin and Nutrition Research 2007 Volume 77, issue 2, pages 89–97

Bibliography

DOI: 10.1024/0300-9831.77.2.89
PubMed: PMID 17896582
Funding: This study was sponsored by Essentys, Lund, Sweden.
Competing interests: Not disclosed in the publication. The study was industry-sponsored by Essentys (Lund, Sweden), the commercial party with an interest in the AKG-calcium salt product being tested.

Study snapshot

Design	Randomised, parallel group, double-blind, placebo-controlled 6-month trial
Model	Postmenopausal women aged 45–65 with established osteopenia (lumbar spine BMD -1.5 to -2.5 SD by DEXA), at least 12 months since menses cessation or oophorectomy
Sample	n = 76 randomised (77 screened); n = 61 in per-protocol analysis (29 AKG-Ca, 32 Ca-only)
Intervention	6 g/day AKG + 1.68 g Ca (as α-ketoglutaric acid calcium salt, 2 chewable tablets three times daily with meals) vs. 1.68 g/day Ca alone (as CaCO3)
Duration	24 weeks (6 months); assessments at baseline, 12 weeks, and 24 weeks
Endpoints	Serum C-terminal cross-linking telopeptide of type I collagen (CTX, bone resorption marker); Serum osteocalcin (bone formation marker); Lumbar spine (L2–L4) bone mineral density by DEXA; Safety: serum calcium, phosphorus, PTH, 1,25(OH)₂D

What the study showed, in plain terms

After menopause, bone breaks down faster than it rebuilds, and this imbalance causes the progressive bone loss that leads to osteoporosis. This 6-month trial tested whether adding alpha-ketoglutarate — a metabolite that increases the body's supply of proline, an amino acid essential for building bone collagen — to a calcium supplement could slow bone breakdown in postmenopausal women who already had osteopenia.

Seventy-six women aged 45 to 65 were randomly assigned to receive either 6 g of AKG combined with 1.68 g of calcium daily, or 1.68 g of calcium alone. Neither the women nor the researchers knew who received which. After 6 months, women taking AKG-calcium had a 37% drop in serum CTX, a blood marker of bone breakdown, while the calcium-only group showed no significant change. Lumbar spine bone density increased 1.6% in the AKG group, though the between-group difference did not reach statistical significance in this short-duration study.

Bone formation, measured by serum osteocalcin, did not change in either group. This pattern — bone breakdown slowed while formation held steady — suggests AKG-calcium acts as a bone-preserving supplement rather than a bone-building one.

Key findings

Serum CTX (bone resorption marker) fell 37.0% from baseline in the AKG-Ca group at 24 weeks (p = 0.006). No significant change occurred in the calcium-only group.
Between-group differences in CTX reached statistical significance at both 12 and 24 weeks (p = 0.03), favouring AKG-Ca.
Serum osteocalcin (bone formation marker) was unchanged by either treatment, indicating AKG-Ca acts as an anti-resorptive without stimulating formation.
Lumbar spine (L2–L4) BMD increased 1.6% from baseline in the AKG-Ca group (p = 0.04); the between-group difference vs. calcium alone was 0.9% and did not reach significance (p = 0.47).
Serum PTH and 1,25(OH)₂D were not altered by either treatment.
Adverse event rates were similar between groups. Mild dyspepsia was the most common AE in the AKG-Ca group (6 vs 1), typically transient and not leading to discontinuation; dropout rates were identical (4 vs 4).
The percentage CTX reduction is comparable to calcitonin (~33%) and raloxifene (~30%) but smaller than bisphosphonate therapy (~57%) reported in other trials.

What this study can and cannot tell us

Duration was only 6 months, which is short for a bone outcome study. Bisphosphonate and hormone therapy trials typically require 2–3 years to demonstrate BMD and fracture benefit. The 0.9% between-group BMD difference is within the coefficient of variation of the DEXA measurement (~1.2%) and cannot support conclusions about long-term bone mass preservation from this trial alone.

The trial was industry-sponsored by Essentys, Lund, Sweden — the commercial party with an interest in the AKG product tested. No formal author conflict-of-interest disclosures are provided in the publication, which was standard for the era but limits reader ability to weigh potential bias.

Fracture incidence — the outcome that matters clinically — was collected only as adverse events and no fractures occurred in either group during the 6-month window. The trial was not powered for fracture prevention.

Participants were osteopenic, not osteoporotic, and had only slightly reduced baseline BMD. Whether the same CTX reduction translates to fracture prevention in higher-risk populations remains untested.

The population was drawn from a single region of eastern Poland and generalisability to other ethnic groups and dietary contexts has not been established.