Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States

Pharmacoepidemiol Drug Saf. 2020 Aug;29(8):854-863. doi: 10.1002/pds.5037. Epub 2020 Jun 14.


Purpose: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications.

Methods: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights.

Results: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = -0.6%, 95% CI: -1.1, -0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations.

Conclusions: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies.

Keywords: bisphosphonate; comparative analyses; denosumab; negative control; osteoporosis; pharmacoepidemiology; residual confounding; zoledronic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Bone Density Conservation Agents / administration & dosage
  • Bone Density Conservation Agents / adverse effects*
  • Confounding Factors, Epidemiologic
  • Denosumab / administration & dosage
  • Denosumab / adverse effects*
  • Diphosphonates / administration & dosage
  • Diphosphonates / adverse effects*
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Female
  • Humans
  • Infusions, Intravenous
  • Injections, Subcutaneous
  • Middle Aged
  • Osteoporosis, Postmenopausal / drug therapy*
  • Sensitivity and Specificity
  • United States / epidemiology
  • Zoledronic Acid / administration & dosage
  • Zoledronic Acid / adverse effects*


  • Bone Density Conservation Agents
  • Diphosphonates
  • Denosumab
  • Zoledronic Acid