New Research Shows Bisphosphonates Prevent Osteoporosis-Related Hip Fractures

Osteoporosis, a decline in bone mass and density, makes bones more susceptible to fracture. The condition is especially common in women who have gone through menopause. It also is linked to the extended use of steroid medications, as well as excessive alcohol use, smoking, low calcium and vitamin D intake, and lack of weight-bearing exercise.[1]

Often a “silent” illness until it is diagnosed, osteoporosis may render bones so fragile that they break as a result of minor falls or actions like bending, lifting or coughing.[2] Hip fractures are among the most health-threatening consequences of osteoporosis.

Recently published research demonstrated that bisphosphonate drugs are useful for preventing osteoporosis-related hip fractures, but that continuous bisphosphonate therapy beyond five years appears to offer no additional benefit for preventing such fractures.

Our assessment of bisphosphonates

Bisphosphonate medications are considered a first-line treatment for reducing fracture risk in osteoporosis. Public Citizen’s Health Research Group concurs with that general characterization but designates bisphosphonates as Limited Use to reduce fracture risk.[3] We have concluded that bisphosphonates should only be used to treat those with a high fracture risk and that continuous treatment with such drugs generally should only last for up to five years.

Additionally, we believe such limited use should be restricted to three bisphosphonate drugs: alendronate (BINOSTO, FOSAMAX), ibandronate (BONIVA) and risedronate (ACTONEL, ATELVIA). We have designated the injectable zoledronic acid (RECLAST) as Do Not Use because it increases the risk of kidney toxicity and resides in bone for a long period, thereby preventing rapid dose reductions that might be needed to address unanticipated adverse effects.

Hip fracture outcomes

A recent review estimated that the one-year mortality rate for those experiencing a hip fracture was 12-37%, though such death rates have been trending downward in recent years.[4] This review further cited one recent large observational study in women older than 70 showing that hip fractures were not associated with an increased risk of death in the year of recovery, while also noting that approximately half of those who experience hip fracture never recover sufficiently to live independently.[5]

Thus, hip fractures in patients with osteoporosis are a substantial cause of disability and death. Treatments that reduce the risk of such fractures are integral to managing osteoporosis.

New systematic review

Researchers in Japan conducted a systematic review of randomized clinical trials that assessed the effectiveness of bisphosphonates for prevention of hip fractures and published their results in the Journal of Bone and Mineral Metabolism in September 2020.[6] They identified eight high-quality randomized, placebo-controlled trials that together enrolled a total of approximately 27,000 subjects.

Seven trials enrolled only women, whereas in the other trial, about a quarter of the subjects were men. The average age of the subjects ranged from 68 years to 83 years. For all eight trials combined, 58% of the subjects had prior osteoporosis-related fractures, which placed them at particularly high risk of additional fractures.

Subjects in the eight trials were randomly assigned to receive a bisphosphonate or a placebo and then followed for two to four years. The researchers found that for subjects who received a bisphosphonate, the risk of a hip fracture during follow-up was reduced by 34% compared with subjects who received a placebo. This difference was highly statistically significant. Additional analyses suggested that bisphosphonates were most effective in reducing the risk of hip fracture in patients who had a prior history of osteoporosis-related fractures.

Evidence that bisphosphonate therapy is not useful beyond five consecutive years

A Journal of the American Medical Association (JAMA) Network Open observational study published in December 2020 used prescription data from a large health-management organization serving California, Kaiser Permanente, to identify 29,685 women who had been prescribed bisphosphonates for an initial five-year period.[7] These women had filled at least 60% of their bisphosphonate prescriptions over a continuous five-year period between January 1997 and September 2014.

The women had a median age of 71 following the initial five-year period of bisphosphonate treatment. Among 11,529 women who had a bone-density measurement following the initial five-year period of bisphosphonate treatment, 37% had very low bone density meeting the criteria for osteoporosis, but 57% had moderately low bone density thus meeting the criteria for the less serious diagnosis of osteopenia.

The JAMA Network Open researchers then used a quantitative model to retrospectively compare rates of hip fracture that occurred after the initial continuous five-year period of bisphosphonate therapy between three subgroups:

• women who discontinued bisphosphonate therapy after the initial five years of therapy;
• women who received two additional years of bisphosphonate treatment for a total of seven continuous years of therapy; and
• women who received an additional five years of bisphosphonate treatment for a total of 10 continuous years of therapy.

In total, there were 507 hip fractures during the follow-up period, which was the five years after the initial five years of bisphosphonate treatment. For most (82%) of the women, follow-up data was available for the full five follow-up years, with 11,105 completing at least seven years of bisphosphonate therapy and 2,725 completing 10 years.

The researchers found that during the five-year follow-up period, hip-fracture rates were not statistically different between the three treatment regimens. Notably, these results were statistically adjusted to account for variables known to influence future fracture risk, including prior fracture, education and income, race, age, body mass index, bone density, tobacco use and other diseases.

What You Can Do

If you are a woman age 65 or older, ask your doctor to assess your fracture risk, looking at all your risk factors and not just your bone density. You can calculate your fracture risk score using the online calculator at https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9. If you are at high risk of fracture (meaning your risk of hip fracture is 3% or more over the next 10 years) or you already have experienced a hip or vertebral fracture, talk to your doctor about your calcium and vitamin D intake, your exercise regimen and whether you should be prescribed an oral bisphosphonate.

Use bisphosphonates for no more than five consecutive years. After this time period, you should talk with your doctor about either taking a break from treatment for several years or stopping treatment permanently, depending on your individual risk at that time.

References

[1] National Institute of Arthritis and Musculoskeletal and Skin Disease. Osteoporosis overview. October 2019. https://www.bones.nih.gov/health-info/bone/osteoporosis/overview. Accessed February 8, 2021.

[2] Ibid.

[3] A Guide to Treatments for Osteoporosis. Worst Pills, Best Pills News. May 2015. https://www.worstpills.org/member/newsletter.cfm?n_id=960. Accessed January 20, 2021.

[4] Morrison RS, Siu AL. Hip fracture in adults: Epidemiology and medical management. UpToDate. Jun 17, 2020.

[5] Ibid.

[6] Tsuda T, Hashimoto Y, Okamoto Y, et al. Meta-analysis for the efficacy of bisphosphonates on hip fracture prevention. J Bone Miner Metab. 2020;38(5):678-686.

[7] Izano MA, Lo JC, Adams AL, et al. Bisphosphonate treatment beyond 5 years and hip fracture risk in older women. JAMA Netw Open. 2020;3(12):e2025190.