Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians

Ann Intern Med. 2023 Feb;176(2):182-195. doi: 10.7326/M22-0684. Epub 2023 Jan 3.


Background: The prevalence of osteoporosis is increasing in the United States.

Purpose: To evaluate low bone mass and osteoporosis treatments to prevent fractures.

Data sources: Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022.

Study selection: Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies (n ≥1000) for harms.

Data extraction: Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE).

Data synthesis: We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE).

Limitation: Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years.

Conclusion: Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare.

Primary funding source: American College of Physicians. (PROSPERO: CRD42021236220).

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Adult
  • Aged
  • Alendronate / adverse effects
  • Bone Density Conservation Agents* / adverse effects
  • Denosumab / adverse effects
  • Diphosphonates / adverse effects
  • Female
  • Fractures, Bone* / prevention & control
  • Humans
  • Male
  • Network Meta-Analysis
  • Osteoporosis* / complications
  • Osteoporosis* / drug therapy
  • Osteoporosis, Postmenopausal* / complications
  • Osteoporosis, Postmenopausal* / drug therapy
  • Physicians*
  • Spinal Fractures* / prevention & control
  • Systematic Reviews as Topic
  • Teriparatide / adverse effects


  • Bone Density Conservation Agents
  • Teriparatide
  • Alendronate
  • Denosumab
  • Diphosphonates