There is a hormone that is almost always discussed in relation to sleep, and almost never in relation to bones. Melatonin, produced by the pineal gland, has a clinical history built primarily around circadian rhythms and sleep disorders. But a meta-analysis published in Frontiers in Nutrition in 2026 suggests the matter is more nuanced than standard clinical practice would imply.
The systematic analysis by Du and Tan examined 10 RCTs conducted between 2015 and 2024, involving 497 women in the peri- or post-menopausal phase. The aim was to evaluate the effect of melatonin supplementation on bone mineral density, sleep quality, menopausal symptoms, mood, sexual function, BMI and insulinemia.
The picture that emerges is partly expected, and partly not.
Melatonin and bone density: the most relevant signal
The primary outcome was bone mineral density (BMD), measured by DXA or quantitative computed tomography. Two RCTs provided data: Amstrup et al. and Maria et al.
The Amstrup study documented an increase in BMD at the femoral neck in groups treated with melatonin at 3 mg, with a statistically significant dose-dependent correlation: the higher the dose, the more marked the benefit. Improvements were also documented at the lumbar spine level in the 3 mg group. The MOTS study by Maria et al. confirmed the same signal: the combination therapy group showed significantly higher bone density than placebo, both at the femoral neck and at the lumbosacral spine.
A critical aspect: both studies used combined formulations, melatonin paired with calcium and vitamin D in the case of Amstrup, melatonin with strontium citrate, vitamin D3 and vitamin K2 in the case of Maria. This prevents isolating melatonin’s independent contribution. The methodological heterogeneity also precluded the possibility of aggregating the data in a pooled analysis.
Why might melatonin influence bone density? On a biological level, preclinical studies indicate that melatonin stimulates osteoblast differentiation, inhibits osteoclast activity through the RANKL pathway and reduces oxidative stress in bone tissue. A triple action that, if confirmed in controlled clinical settings, positions melatonin as a modulator of bone metabolism with its own mechanisms.
Secondary outcomes: inconclusive evidence, not absence of effect
A finding that risks being misread: the lack of statistical significance does not equate to proof of inefficacy.
The analysis aggregated data on six secondary outcomes. The emerging pattern is consistent: wide confidence intervals, high heterogeneity, limited sample sizes.
- Sleep: no significant overall improvement. The studies were very different from each other in methodology and measurement scale, making direct comparison difficult.
- Menopausal symptoms: no relevant reduction in hot flushes or other disorders. The variability between studies is the highest in the entire analysis.
- Sexual function: no difference compared to placebo. The available data are still too limited to draw conclusions.
- BMI: no significant variation in body weight. The wide range of doses used across studies made it difficult to assess any metabolic effects.
- Anxiety and depression: no difference compared to placebo, but sample sizes were small. Results to be interpreted with caution, not as definitive proof of inefficacy.
The authors are explicit: these data should be interpreted as inconclusive, not as evidence of absence of effect. Wide confidence intervals signal imprecision, not null efficacy.
What factors might moderate melatonin’s response on sleep? The literature suggests that the baseline profile is decisive: women with diagnosed sleep disorders showed positive individual improvements in some of the included studies, a signal that the aggregate analysis fails to capture due to the reduced sample sizes.
Dosages, formulations and clinical heterogeneity
The analysed dosage range was considerable: from 1 mg up to 3 g of melatonin per day, with treatment durations between 3 and 12 months. The most frequently used dose in the RCTs was 3 mg, the one associated with the most relevant results on BMD at the femoral neck.
In Europe, melatonin is available as a supplement at sub-mg dosages or, in some countries, as a prescription drug with an indicative dose of 2 mg nightly for sleep. Regulatory variability overlaps with clinical variability that the meta-analysis fails to resolve.
The formulations studied were predominantly oral, with evening or bedtime administration. One study also included a morning administration in addition to the evening one, at 3 mg plus 5 mg, for a total of 8 mg/day, the highest dosage in the entire analysis.
Melatonin safety: an element not to be overlooked
The short-term safety profile was comparable to placebo in all the examined studies: adverse effects were rare and similarly distributed between the two groups.
A more recent observation deserves attention: an observational study presented at the AHA Scientific Sessions 2025 identified an association between prolonged melatonin use (over 12 months) and an increased risk of incident heart failure (HR 1.89), hospitalization for heart failure (HR 3.44) and all-cause mortality (HR 2.09) in patients with chronic insomnia.
The RCTs included in the meta-analysis were not designed to evaluate cardiovascular endpoints and do not allow definitive conclusions on this front. The observational data is nonetheless a clinical signal that requires confirmation in dedicated prospective trials, and that those formulating melatonin-based products cannot ignore.
Formulative implications: melatonin in combination
The data that current research produces emerges not from studies on melatonin as monotherapy, but from formulations that include calcium, vitamin D, strontium or myo-inositol. This is not only a scientific limitation: it reflects the real formulative practice of the supplements sector.
The biological synergy has a precise plausibility: calcium and vitamin D provide the substrates for bone mineralization, while melatonin modulates cellular activity. Preclinical studies suggest that the osteogenic effect of melatonin is amplified in the presence of adequate concentrations of these micronutrients. Three-arm trials are needed, melatonin alone, combination therapy and placebo, to isolate the specific contribution.
For those working in supplement development in the menopause area, the available literature points in a direction: melatonin as a component of multitarget formulations for bone health, not as an isolated ingredient for symptom management. A scientifically stronger and regulatorily more sustainable position.
If your company is interested in developing melatonin-based formulations
Source: Du J and Tan Y (2026) A systematic review and meta-analysis of randomized controlled trials investigated the effects of melatonin supplementation on bone mineral density, quality of life, and sleep in menopausal women. Front. Nutr. 13:1687221. doi: 10.3389/fnut.2026.1687221
