What is the effect of Pioglitazone on bone health?

From the Guidelines

Pioglitazone has a negative effect on bone health, increasing the risk of fractures.

Key Points

• The use of pioglitazone is associated with an increased risk of bone fractures, as noted in several studies 1.
• This increased risk of fractures is a significant consideration in the management of patients with type 2 diabetes, particularly in postmenopausal women or elderly men 1.
• The mechanism behind this increased risk is not fully understood, but it may be related to the effects of pioglitazone on bone metabolism.
• Other medications may be preferable for patients with type 2 diabetes who are at risk of fractures, due to their safer bone health profiles 1.
• The benefits of pioglitazone in improving glucose and lipid metabolism, as well as its potential to reverse steatohepatitis, must be weighed against the potential risks to bone health 1.

Important Considerations

• Pioglitazone causes dose-dependent weight gain, which may also contribute to the increased risk of fractures 1.
• The risk of fractures associated with pioglitazone may be mitigated by using lower doses, although further study is needed to confirm this 1.
• Patients taking pioglitazone should be monitored for signs of fracture risk and managed accordingly to minimize this risk.

From the FDA Drug Label

In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9. 5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2. 5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2. 1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care

The effect of Pioglitazone on bone health is an increased risk of fractures, particularly in female patients. The majority of fractures observed were nonvertebral fractures. No increased risk was observed in male patients. It is recommended to consider the risk of fracture and assess and maintain bone health in patients treated with Pioglitazone, especially females 2.

• Key points:
  • Increased incidence of bone fracture in female patients
  • No increase in fracture rates in male patients
  • Majority of fractures were nonvertebral fractures
  • Risk of fracture should be considered in patient care, especially in female patients

From the Research

Effect of Pioglitazone on Bone Health

• Pioglitazone therapy has been shown to decrease bone mass density (BMD) and increase fat mass, leading to an increased risk of fractures 3.
• The molecular mechanism of pioglitazone can lead to an imbalance in bone metabolism, resulting in decreased BMD and increased bone resorption 3, 4, 5.
• Studies have found that pioglitazone increases bone resorption markers, such as serum and urinary type 1 cross-linked N-telopeptide (NTX) and type 1 cross-linked C-telopeptide (CTX), and decreases bone formation markers, such as bone alkaline phosphatase (BAP) 4, 5.
• Pioglitazone has been shown to decrease BMD at various skeletal sites, including the lumbar spine, total hip, and femoral neck, although the effects on fracture rates are unclear 3, 6.
• The use of pioglitazone in combination with other medications, such as vildagliptin, may help to mitigate its negative effects on bone health 7.

Bone Metabolism and Pioglitazone

• Pioglitazone has been found to decrease osteoblast surface and mineralizing surface, while increasing osteoclast surface and number, leading to an imbalance in bone metabolism 5.
• The medication has also been shown to increase the expression of sclerostin, a protein that inhibits bone formation, and decrease the expression of bone formation markers, such as osteocalcin 7.
• The effects of pioglitazone on bone metabolism may be dose-dependent, with higher doses leading to greater decreases in BMD and increases in bone resorption markers 3, 5.

Clinical Implications

• The use of pioglitazone in patients with type 2 diabetes or impaired glucose tolerance may require careful consideration of its potential effects on bone health 3, 6.
• Clinicians may need to monitor BMD and bone turnover markers in patients taking pioglitazone, particularly those at high risk of osteoporosis or fractures 3, 4.
• Further research is needed to fully understand the mechanisms by which pioglitazone affects bone health and to develop strategies for mitigating its negative effects 6, 7.