Denosumab vs placebo for new vertebral fractures in postmenopausal osteoporosis

Overview

Denosumab vs placebo for new vertebral fractures in postmenopausal osteoporosis

In postmenopausal women with osteoporosis, does denosumab reduce new vertebral fractures versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

10 of 10 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 1 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Denosumab vs placebo for new vertebral fractures in postmenopausal osteoporosis

## PICO
- **Population:** postmenopausal women with osteoporosis.
- **Intervention:** denosumab, including AMG 162 or Prolia terminology.
- **Comparator:** placebo.
- **Primary outcome:** new vertebral fracture.

## Eligibility - P/I/C/design only
Include randomized controlled trials when all of the following are true:
- The population is postmenopausal women with osteoporosis, judged from the title or registry conditions.
- The randomized intervention is denosumab.
- The randomized comparator is placebo.
- The trial is double-blind or placebo-controlled.

Exclude records for wrong population, wrong intervention, wrong comparator, non-randomized design, reviews, extensions without randomized placebo comparison, protocol-only reports, men-only trials, mixed women-and-men osteoporosis trials, cancer-related bone loss, chronic kidney disease or renal insufficiency, pediatric populations, and trials focused on another osteoporosis drug.

Eligibility is not based on whether the abstract reports the target outcome. If an otherwise eligible trial does not report new vertebral fracture with an arm-level count or effect estimate plus 95% CI in the abstract or eligible structured registry results, it is declared absent rather than substituted with another endpoint.

## Outcomes
Primary outcome:
- New vertebral fracture, including phrasings such as new radiographic vertebral fracture, new or worsening vertebral fracture, incidence of new vertebral fracture, primary outcome, primary endpoint, and primary end point.

Secondary outcomes:
- Nonvertebral fracture.
- Hip fracture.

Harm outcomes:
- Serious adverse events.
- Serious infection.

## Analysis Method
The estimand is the risk ratio for denosumab versus placebo. The declared synthesis method is random-effects inverse-variance pooling on log risk ratios using Paule-Mandel tau^2 and HKSJ 95% confidence intervals on t(k-1), with the variance floor `max(1, Q/(k-1))`. Prediction intervals use `mu +/- t(k-1)*sqrt(tau^2+se^2)`. If only one eligible trial reports the outcome, the result is presented as that trial's own effect and no random-effects pooling, tau^2, HKSJ interval, or prediction interval is applicable.

## Comparator
The comparator is Wei et al., "Efficacy and safety of pharmacologic therapies for prevention of osteoporotic vertebral fractures in postmenopausal women," *Heliyon* 2023, PMID 36852077, DOI 10.1016/j.heliyon.2022.e11880, PMCID PMC9958453. It is open access and reports a network meta-analysis of randomized trials in postmenopausal women with osteoporosis; the abstract reports denosumab versus placebo for vertebral fractures as RR 0.33 with 95% CI 0.14 to 0.61.

## Controls
- Positive control: FREEDOM, PMID 19671655.
- Negative control: denosumab in men receiving androgen-deprivation therapy for prostate cancer, PMID 19671656.

Search

Source status (which adapters ran)

Citation chase: NOT_RUN · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: NOT_RUN · PubMed: RAN_OK · Registry-first (AACT): RAN_OK — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

Registry-first recall (reach)

Registry-first RECALL: recovered 0/1 of this topic's known trials (enumerated 115; status RAN_OK). Reachable ceiling 1/1: 1 trial(s) are registered but not enumerated by the committed query (registry vocabulary limit — improvable). Missed: 19671655. Measured 2026-09-11T23:39:14Z. Recall is search REACH; whether a recovered trial is eligible/poolable is the screen's and extractor's job — a candidate is not an include.

Registry landscape & unpublished evidence (AACT)

Of 115 registry records matching the query (broad — reach, not precision): 42 have a linked publication; 26 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 11 are completed ≥12 months ago with neither results nor a linked publication — a loose upper bound on non-publication, inflated by the broad enumeration and by NCT→PMID linkage misses, not a publication-bias claim. AACT 2026-08-30 (local snapshot).

PubMed

19671655[uid]

denosumab[Title] AND prevention[Title] AND fractures[Title] AND postmenopausal[Title] AND osteoporosis[Title]

ClinicalTrials.gov

{"cond": "postmenopausal osteoporosis vertebral fracture", "intr": "denosumab"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 71 records: agreement 70/71, disagreement 1.4% (1 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:04Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

71 records screened; 1 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['19671655'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['19671656'] recovered by the search and correctly EXCLUDED ['19671656'] by rule (same drug/design, wrong topic).

Results

New vertebral fracture (primary)

Nonvertebral fracture

Hip fracture

Harms

Serious adverse events

Serious infection

Comparator

New vertebral fracture: 0.33 (RR), 95% CI 0.14–0.61

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 1 of 1 primary-outcome pooled trials have a registry (AACT) match and are assessed below (all primary-outcome pooled trials assessed).

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT 2026-08-30 + registry-vs-pooled (D5)). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In postmenopausal women with osteoporosis, does denosumab reduce new vertebral fractures versus placebo? (Double-blind placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 3fb64a1e0143); a registry-first search was screened by two independent rule screeners with adjudication (71 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. A single eligible trial contributed an extractable estimate: RR 0.32 (95% CI 0.25 to 0.4); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Certainty. Partial GRADE certainty was low (from 2 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 3fb64a1e0143) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

A single eligible trial contributed an extractable estimate: RR 0.32 (95% CI 0.25 to 0.4); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 1 of 1 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 3fb64a1e0143) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py denosumab-vertebral-fracture

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 1 vs the comparable same-scope comparator k = — NOT-ENUMERABLE. comparator is a 55-node NMA; trial list only in supplement

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 3 of 3 that are checkable from the abstract (0 identical, 3 same-result-different-statistic, 0 conflict; 0 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.