Nutritional Supplementation Combined with Exercise for Musculoskeletal Health in Women: A Systematic Review and Meta-Analysis Evaluating Proteins, Amino Acids, and Creatine across Reproductive Stages.

This was a systematic review and meta-analysis that pooled data from 14 randomized controlled trials (RCTs) to answer one question: Does adding a nutritional supplement (protein, amino acids, or creatine) to a structured exercise program produce better musculoskeletal outcomes than exercise alone (or exercise plus placebo) in women?

The researchers grouped the supplements into three categories:

**Whole-protein supplements** (5 studies): Typically whey protein, soy protein, or milk protein concentrates, dosed at 20–40 grams per day.

**Amino acids and derivatives** (6 studies): Individual amino acids like leucine, branched-chain amino acids (BCAAs), or amino acid blends, dosed at 3–12 grams per day.

**Creatine monohydrate** (3 studies): Dosed at 3–5 grams per day, typically with a loading phase.

The comparator in all studies was either exercise alone (no supplement) or exercise plus a placebo (e.g., maltodextrin, a carbohydrate powder with no protein content).

The primary outcome was **muscle mass**, measured in three ways:

Skeletal muscle mass (total body muscle)

Appendicular lean mass (muscle in arms and legs)

Fat-free mass (everything in the body that isn't fat — muscle, bone, organs, water)

Secondary outcomes included:

**Muscle strength**: Bench press (upper body), leg press (lower body), and handgrip strength

**Bone health**: Bone mineral content (BMC, total grams of bone mineral) and bone mineral density (BMD, grams per square centimeter)

**Body composition**: Body fat percentage and lean mass

**Adverse events**: Any reported side effects

The meta-analysis included **763 women** across 14 randomized controlled trials. The women spanned all reproductive stages:

**Premenopausal** (regular menstrual cycles): Approximately 30% of participants

**Perimenopausal** (irregular cycles, transitioning to menopause): Approximately 25%

**Postmenopausal** (no menstruation for 12+ months): Approximately 45%

Specific characteristics:

Age range: 18–75 years (mean age across studies ranged from 22 to 68)

All were healthy or had low bone mass (osteopenia), but none had diagnosed osteoporosis or severe chronic disease

Body mass index (BMI) range: 19–32 kg/m² (normal weight to overweight)

None were taking hormone replacement therapy or medications known to affect muscle or bone (e.g., corticosteroids)

All were sedentary or recreationally active (not competitive athletes)

Studies were conducted in the United States, Canada, United Kingdom, Australia, Japan, and Taiwan

Study durations ranged from 8 weeks to 12 months (mean: 16 weeks)

The researchers extracted data from each included trial using standardized instruments:

**Muscle mass:**

Dual-energy X-ray absorptiometry (DXA) — the gold standard for measuring body composition. It uses low-dose X-rays to distinguish fat, muscle, and bone. Precision: ~1–2% error.

Bioelectrical impedance analysis (BIA) — a less precise method that sends a small electrical current through the body. Used in 3 of 14 studies. Precision: ~3–5% error.

**Muscle strength:**

One-repetition maximum (1RM) testing for bench press and leg press — the maximum weight a person can lift once with proper form. This is the gold standard for strength assessment.

Handgrip dynamometry — a device that measures isometric grip strength in kilograms. Standardized protocol: 3 attempts per hand, best score recorded.

**Bone health:**

DXA scans of the lumbar spine (L1–L4) and total hip — the clinical standard for diagnosing osteoporosis. Reported as bone mineral density (g/cm²) and bone mineral content (g).

**Adverse events:**

Self-reported questionnaires and medical monitoring during the trial period.

The researchers used Hedges' g as their effect size metric — this is a standardized mean difference that corrects for small sample bias. A Hedges' g of 0.2 is considered small, 0.5 moderate, and 0.8 large.

**Study design:** This is a systematic review and meta-analysis — meaning the authors searched for all existing RCTs on the topic, assessed their quality, and statistically combined their results. This is the highest level of evidence for answering a treatment question, provided the included studies are well-designed.

**Search strategy:** Eight databases were searched from their inception to July 2025: CINAHL, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, MEDLINE/PubMed, Scopus, and Web of Science. Two reviewers independently screened titles/abstracts and full texts. Disagreements were resolved by consensus or a third reviewer.

**Inclusion criteria:**

Randomized controlled trials only (not observational studies, case reports, or reviews)

Women across any reproductive stage (pre-, peri-, or postmenopausal)

Intervention: any nutritional supplement (protein, amino acid, or creatine) combined with a structured exercise program (resistance training, aerobic exercise, or combined)

Comparator: exercise alone or exercise plus placebo

Minimum duration: 8 weeks

Reported at least one outcome of interest (muscle mass, strength, or bone health)

**Exclusion criteria:**

Studies in men only (or mixed-sex studies where women's data couldn't be separated)

Studies in athletes (defined as competitive or elite)

Studies where the supplement was given without exercise

Studies where the exercise program was unsupervised or not described

Studies in women with diagnosed osteoporosis, cancer, or other chronic diseases affecting muscle/bone

**Risk of bias assessment:** Two reviewers independently assessed each trial using the Cochrane Risk of Bias tool (version 2). This evaluates: random sequence generation (was assignment truly random?), allocation concealment (could researchers predict group assignment?), blinding (were participants and assessors unaware of group?), incomplete outcome data (were dropouts accounted for?), selective reporting (were all outcomes reported?), and other biases. Studies were rated as low risk, some concerns, or high risk.

**Statistical approach:** Random-effects meta-analysis was used — this assumes the true effect varies across studies (due to different populations, supplement types, exercise protocols, etc.) and produces a more conservative estimate than fixed-effects models. Heterogeneity was quantified using I² (percentage of variation due to true differences between studies rather than chance). I² values of 25%, 50%, and 75% are considered low, moderate, and high, respectively.

**What this design can prove:**

Whether, on average, adding supplements to exercise produces better outcomes than exercise alone

Whether the effect is consistent across different supplement types and populations

Whether there are subgroups that benefit more (e.g., postmenopausal women, those with low protein intake)

**What this design cannot prove:**

Which specific supplement is best (because the analysis pooled different supplements together)

The optimal dose or timing of supplementation (studies used different protocols)

Long-term effects beyond 12 months (the longest study was 12 months)

Whether supplements work without exercise (all studies included exercise)

Causal mechanisms (the meta-analysis can show an association but not explain why it occurs)

**Major methodological weaknesses:**

**High heterogeneity** in supplement types: Pooling whey protein, BCAAs, and creatine together is problematic because they work through different biological mechanisms. The authors acknowledge this but argue it enhances "real-world applicability."

**Short durations**: Most studies were 8–16 weeks. Muscle and bone changes take months to years to manifest, so longer studies might show different results.

**Small sample sizes**: Individual studies ranged from 20 to 120 women. Small studies are more prone to random error and publication bias.

**Variation in exercise protocols**: Some studies used supervised resistance training 3x/week; others used home-based aerobic exercise. The quality and intensity of exercise varied widely.

**Dietary control**: Few studies monitored participants' total protein intake from food. If participants were already eating adequate protein (≥1.2 g/kg/day), adding supplements may not provide additional benefit.

**Risk of bias**: Of the 14 included trials, 5 had "some concerns" and 2 were rated "high risk" — primarily due to lack of blinding (participants knew they were getting a supplement) and incomplete outcome data (high dropout rates).

**Primary outcome — Muscle mass (no significant effects):**

**Skeletal muscle mass** (4 studies, n=201): Hedges' g = 0.065 (95% CI: -0.353 to 0.482, p = 0.762). This means the supplement group gained essentially the same amount of muscle as the exercise-only group. The confidence interval is wide and crosses zero, meaning the true effect could be negative (supplements worse) or moderately positive.

**Appendicular lean mass** (5 studies, n=268): Hedges' g = 0.197 (95% CI: -0.177 to 0.571, p = 0.302). A small positive trend, but not statistically significant. The confidence interval includes zero.

**Fat-free mass** (8 studies, n=412): Hedges' g = 0.069 (95% CI: -0.110 to 0.249, p = 0.447). Essentially no effect. This was the most well-powered analysis (largest sample size), and the result is clear: no meaningful benefit.

**Secondary outcome — Muscle strength (mixed results):**

**Bench press strength** (6 studies, n=298): Hedges' g = 0.279 (95% CI: 0.008 to 0.550, p = 0.043). This is a small but statistically significant improvement. In practical terms, this translates to approximately 2–4 kg more weight lifted in the supplement group compared to exercise alone.

**Handgrip strength** (4 studies, n=186): Hedges' g = 0.412 (95% CI: 0.039 to 0.786, p = 0.031). A moderate effect. This translates to approximately 2–3 kg more grip force in the supplement group.

**Leg press strength** (5 studies, n=252): Hedges' g = 0.148 (95% CI: -0.102 to 0.398, p = 0.246). No significant effect. Lower-body strength did not improve with supplementation.

**Secondary outcome — Bone health (no significant effects):**

**Bone mineral content** (3 studies, n=156): Hedges' g = 0.195 (95% CI: -0.281 to 0.671, p = 0.421). No significant effect. The confidence interval is very wide, indicating imprecision.

**Bone mineral density** (5 studies, n=278): Hedges' g = 0.087 (95% CI: -0.129 to 0.303, p = 0.430). No effect. Bone density was essentially identical between supplement and exercise-only groups.

**Subgroup analyses (exploratory):**

**Creatine vs. protein/amino acids**: When the authors separated creatine studies from protein/amino acid studies, the strength improvements were driven primarily by creatine. For bench press, creatine studies showed g = 0.41 (p = 0.04) while protein studies showed g = 0.12 (p = 0.52). However, this subgroup analysis included only 3 creatine studies (n=98 women), so it should be interpreted cautiously.

**Menopausal status**: No significant differences between pre-, peri-, and postmenopausal women, but the number of studies per subgroup was too small to draw firm conclusions.

**Duration**: Studies lasting ≥12 weeks showed slightly larger effects than shorter studies, but the difference was not statistically significant.

**Adverse events:**

No significant increase in adverse events in the supplement groups compared to placebo/exercise-only groups

Reported side effects were mild: gastrointestinal discomfort (bloating, diarrhea) in 5–10% of participants taking whey protein or creatine; no serious adverse events

To translate these statistics into plain English:

**Muscle mass**: Adding supplements to exercise produced essentially zero additional muscle gain. If you exercise for 12 weeks, you might gain 1–2 kg of muscle. Adding a protein shake or creatine will not increase that number meaningfully — you'd gain maybe 0.1–0.2 kg more, which is within the measurement error of a DXA scan.

**Upper-body strength**: The supplement group could bench press approximately 2–4 kg more than the exercise-only group after 12–16 weeks. This is roughly equivalent to the difference between lifting a full grocery bag vs. a half-full one. For handgrip, the improvement was about 2–3 kg — noticeable if you're opening jars, but not life-changing.

**Lower-body strength**: No benefit. Leg press strength was essentially identical between groups. If you're doing squats and lunges, supplements won't help you lift more.

**Bone density**: No benefit. After 12 months of exercise plus supplements, bone density was the same as exercise alone. For context, postmenopausal women lose about 1–3% of bone density per year. Exercise alone can slow this to 0.5–1% loss. Adding supplements did not further reduce that loss.

**Practical comparison**: The strength improvements from supplements (g = 0.28–0.41) are roughly one-third to one-half the size of the strength improvements from exercise alone (typically g = 0.8–1.2 for resistance training vs. no exercise). So supplements provide a small boost on top of a much larger exercise effect.

**What the authors acknowledge:**

1. **Heterogeneity of interventions**: Pooling whey protein, BCAAs, and creatine together limits mechanistic interpretability. These compounds work through different pathways — protein provides amino acid building blocks, creatine enhances energy metabolism — and they may have different effects.

2. **Short intervention durations**: Most studies were 8–16 weeks. Muscle hypertrophy (growth) plateaus after 6–12 months, and bone remodeling cycles take 3–6 months. Longer studies (≥12 months) might show different results, particularly for bone density.

3. **Small number of studies per outcome**: For some analyses (e.g., bone mineral content, skeletal muscle mass), only 3–4 studies were available. This limits statistical power and precision.

4. **Variability in exercise protocols**: Some studies used supervised, progressive resistance training (optimal for muscle gain), while others used unsupervised home exercise (less effective). This variability may have diluted the supplement effect.

5. **Lack of dietary control**: Few studies measured or controlled participants' total protein intake from food. If participants were already consuming adequate protein (≥1.2 g/kg/day), adding supplements may not provide additional benefit.

6. **Publication bias**: The authors tested for publication bias using funnel plots and Egger's test, but with only 14 studies, these tests have low sensitivity. It's possible that small studies with null results were never published.

**Additional limitations a critical reader would note:**

7. **Industry funding**: Of the 14 included trials, 6 were funded by supplement companies (whey protein manufacturers, creatine brands). Industry-funded studies are more likely to report positive results. The authors did not conduct a sensitivity analysis excluding industry-funded studies.

8. **Blinding issues**: Protein supplements have a distinct taste and texture. Only 8 of 14 studies used a placebo that was matched for taste and appearance. In the other 6 studies, participants likely knew whether they were in the supplement group, which