Why do bisphosphonates (Bone Protective Agents) cause bone pain?

From the Guidelines

Bisphosphonates can cause pain due to their effects on bone metabolism and immune responses, with the most common pain syndrome being an acute phase reaction that occurs in about 30% of patients, especially after the first intravenous dose of medications like zoledronic acid 1.

Mechanisms of Pain

The pain caused by bisphosphonates can be attributed to several mechanisms, including:

• Acute phase reaction: This reaction typically causes flu-like symptoms with muscle aches, bone pain, and joint discomfort that usually begins within 24-48 hours after administration and resolves within 3-7 days 1.
• Inhibition of osteoclast activity: Bisphosphonates inhibit osteoclast activity, which temporarily disrupts normal bone remodeling and can lead to microfractures, causing severe musculoskeletal pain that may begin days to months after starting therapy and may be persistent 1.
• Release of inflammatory cytokines: Bisphosphonates can trigger the release of inflammatory cytokines like interleukin-6 and tumor necrosis factor-alpha, contributing to pain symptoms 1.

Rare but Serious Causes of Pain

In rare cases, bisphosphonates may cause:

• Osteonecrosis of the jaw: This condition can cause severe pain and occurs in 1% to 10% of patients with intravenous bisphosphonate used at the higher doses for treating metastatic bone disease 1.
• Atypical femoral fractures: These fractures can cause severe pain and have been reported in patients on long-term bisphosphonate therapy, although a causal relationship has not been established with certainty 1.

Management of Pain

Patients experiencing severe or persistent pain should consult their healthcare provider, as dosage adjustment, switching to a different bisphosphonate, or pre-medication with acetaminophen or NSAIDs before administration may help manage these side effects.

From the FDA Drug Label

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates [see Adverse Reactions (6. 2)]. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.

Bisphosphonates can cause musculoskeletal pain, including severe and occasionally incapacitating bone, joint, and/or muscle pain. The exact mechanism is not specified in the label, but it is a known adverse reaction associated with bisphosphonate use 2, 3.

• The time to onset of symptoms can vary from one day to several months after starting the drug.
• Most patients experience relief of symptoms after stopping the medication.
• However, a subset of patients may have recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
• It is recommended to consider discontinuing use if severe symptoms develop.

From the Research

Bisphosphonates and Pain

• Bisphosphonates are known to cause severe and sometimes incapacitating muscle, joint, and bone pain in some patients, particularly those taking oral bisphosphonates once a week 4.
• This type of pain affects between 2% and 5% of patients, especially those treated for osteoporosis 4.
• The mechanisms underlying the analgesic effects of bisphosphonates are still largely elusive, but there is increasing evidence for clinical efficacy of bisphosphonates in chronic pain states 5.

Incidence of Pain

• Comparative trials and reports by healthcare professionals show that severe and sometimes incapacitating muscle, joint, and bone pain can occur days, months, or years after beginning long-term oral bisphosphonate therapy 4.
• Discontinuation of bisphosphonate therapy can be tried and may represent a better option than escalation of analgesic therapy 4.

Comparison of Bisphosphonates

• Different bisphosphonates have varying effects on the central and peripheral skeleton, with some studies showing greater effects on the spine than the hip 6.
• Ibandronate and alendronate have been shown to have greater effects on the lumbar spine and total body BMD than risedronate 6.
• However, treatment effects on peripheral measurements did not differ between the three bisphosphonates 6.

Switching to Denosumab or Bisphosphonates

• Switching to denosumab after completion of teriparatide treatment in women with severe postmenopausal osteoporosis resulted in higher additional lumbar spine BMD gain compared to bisphosphonates treatment 7.
• Multivariate analysis showed that BMD gain at the lumbar spine was negatively associated with bisphosphonate versus denosumab treatment 7.