Repair and pain
Does it protect bone?
Bone density is a scan result. Fracture is an event. Trials that measured fractures are worth far more than trials that measured density, and this separates them.
2,162
people in trials
7
human studies
0
compounds, animal or cell only
0
trials found nothing
Measured in people
Ranked by how many people, which is a fact about the evidence and not a judgement about the compound. The one at the top is the most studied, which is not the same as the best. Counts are never added across compounds, because the same person can appear in more than one trial.
- 2,039 people3 human studies
2,000 New Zealand women aged 65 or older with osteopenia, randomised to four infusions of 5 mg zoledronate or saline at 18-month intervals over six years. Fragility fracture occurred in 190 on placebo and 122 on zoledronate, hazard ratio 0.63 (95 percent CI 0.50 to 0.79). Number needed to treat 15. This is the large trial in older women, and its primary endpoint was fracture, not mortality.
New England Journal of Medicine, 2018 · 2,000 people
Adverse event analysis of that same 2,000-woman trial. Myocardial infarction in 39 women on placebo against 24 on zoledronate (hazard ratio 0.60, 95 percent CI 0.36 to 1.00). Total cancers reduced, hazard ratio 0.67 (0.51 to 0.89). Hazard ratio for death 0.65 (0.40 to 1.06, p equals 0.08), and 0.51 (0.30 to 0.87) in women without an incident fragility fracture. The authors state these apparent effects justify further appropriately powered trials with these nonskeletal conditions as primary endpoints.
Journal of Bone and Mineral Research, 2020 · 39 people
HORIZON Recurrent Fracture Trial, NCT00046254. 1,065 assigned to yearly 5 mg intravenous zoledronic acid and 1,062 to placebo within 90 days of hip fracture repair, mean age 74.5, median follow-up 1.9 years. Primary endpoint new clinical fracture: 8.6 percent against 13.9 percent, a 35 percent reduction. In the safety analysis 101 of 1,054 (9.6 percent) on drug and 141 of 1,057 (13.3 percent) on placebo died, a 28 percent reduction in all-cause death, p equals 0.01. Mortality was not the primary endpoint. Commonest adverse events were pyrexia, myalgia and bone and musculoskeletal pain; no osteonecrosis of the jaw was reported.
New England Journal of Medicine, 2007 · no headcount in the line
- 123 people1 human study
123 elderly hip-fracture patients: gait speed improved and IGF-1 rose, but most functional measures did not, and the trial was terminated early over a congestive heart failure safety signal.
Archives of Gerontology and Geriatrics, 2011 · 123 people
- no headcount stated1 human study
The bone arm of RESHAW. After 12 months on 75 mg twice daily, lumbar spine bone density rose 0.016 g/cm2 versus placebo, femoral neck T-score improved 0.070, C-terminal telopeptide (a resorption marker) fell, and FRAX ten-year major and hip fracture probability dropped. The benefit was larger in women with poor bone biomarker status and in those also taking vitamin D plus calcium. Density and markers, not fractures.
Journal of Bone and Mineral Research, 2020 · no headcount in the line
- no headcount stated1 human study
Randomised, up to 24 months of oxandrolone in severely burned children with five-year follow-up. Significant improvement in whole-body bone mineral content, lumbar spine bone mineral content and density, and height velocity, with treated children showing significantly greater height velocity throughout the first two years post-burn. Fewer treated children had bone density z-scores below minus 2.0, indicating reduced future fracture risk. Two years of treatment produced significantly greater gains than twelve months. No adverse effects were attributed to long-term administration in this cohort.
Shock, 2016 · no headcount in the line
- no headcount stated1 human study
266 elderly and older persons assessed over six to eight years, with thymalin and epithalamin applied during the first two to three years. Acute respiratory disease incidence fell 2.0 to 2.4-fold, with reduced clinical ischaemic heart disease, hypertension, deforming osteoarthrosis and osteoporosis against control. Mortality fell 2.0 to 2.1-fold with thymalin, 1.6 to 1.8-fold with epithalamin and 2.5-fold with both, and a separate group treated with both annually for six years had a 4.1-fold lower mortality rate. Single group, no described blinding or randomisation, never replicated.
Neuro Endocrinology Letters, 2003 · no headcount in the line
Why the trial record looks like this
A missing trial is usually a missing sponsor. Nobody runs a nine-figure programme on a molecule they cannot own, so the compounds with the thinnest human records are often the oldest and most freely available ones rather than the weakest. Taking Zoledronic acid as the example, because it states the problem most clearly:
This page deliberately does not settle the disagreement, because the field has not.
The case that the mortality effect is real: it came from a large double-blind placebo-controlled randomised trial, not an observational cohort, so confounding by indication cannot explain it. It was large in absolute terms, 40 fewer deaths. A second independent randomised trial in a different country and a healthier population found effects pointing the same way for cancer, myocardial infarction and death. And a plausible non-skeletal mechanism has since been demonstrated in cells and aged mice, with zoledronic acid killing senescent cells selectively and reducing circulating SASP factors.
The case that it is not: it was not the primary endpoint, and the investigators' own mediation analysis could not find a route for it, with adjustment for acute events during follow-up abolishing the effect entirely. When 38 randomised trials covering 101,642 people were pooled, the mortality benefit disappeared, and the zoledronate-only subset remained non-significant with real heterogeneity between studies. The Reid trial's death hazard ratio crossed 1. No trial has ever been run with mortality as the question it was designed to answer.
What both camps agree on is the remedy, and it is the same sentence in the 2019 meta-analysis and in the 2020 Reid analysis: an appropriately powered trial with these endpoints as the primary outcome is needed. That trial has not reported. Until it does, zoledronic acid is a well-evidenced fracture drug with an unexplained mortality signal attached, which is a genuinely interesting thing to be and is not the same thing as a proven anti-ageing drug.
One conflict of interest worth stating: the senior author of the meta-analysis that found no mortality benefit discloses grants and personal fees from Amgen, which markets a competing osteoporosis drug. This is disclosed in the paper. It is noted here because readers should weigh it themselves, not because it invalidates a meta-analysis of 38 randomised trials.
A compound appears here only when a citation on its own page states this outcome and reports a result for it; naming it is not enough. Human, animal and cell work are counted separately and never merged. Participant counts are read from the study lines and deliberately undercount. Nothing here is advice, and nothing here is a recommendation to take or to avoid anything.