What we know about PPIs and bone
Because PPIs are widely used, it is of paramount importance to understand the precise effects through which use of a PPI may affect bone mineral metabolism and influence fracture risk.
Targownik and Leslie discuss the evidence supporting an association between PPIs and fragility fracture, the association between PPIs and calcium malabsorption, and the underlying condition that predisposes patients who have osteoporosis to fracture. They also explore the possible mechanisms by which PPIs may increase the risk of fracture. After conducting a PubMed search and review of the literature, they found limited evidence supporting the FDA’s assertion that PPIs may increase the risk of fracture. Other findings:
- Multiple analyses have demonstrated a modest association between chronic PPI use and an increased risk of fracture
- No studies have convincingly demonstrated that PPIs cause fracture
- Overall, PPI use does not interfere with calcium absorption in most instances; therefore, it is unlikely that PPIs influence the risk of fracture by interfering with the absorption of dietary calcium
- Dual-energy x-ray absorptiometry (DEXA) testing demonstrates no consistent effect of PPIs on BMD
- Preliminary evidence suggests that PPIs may interfere with normal osteoclastic function, although it is unclear whether such interference influences the risk of fracture.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
PPIs are the most potent inhibitors of acid secretion available; standard once-daily dosing may lead to a 90% decrease in gastric acid secretion and will maintain an intragastric pH level above 4 for as long as 70% of any 24-hour period.
PPIs are known to be effective for treating symptoms of GERD and preventing GERD-related complications. These drugs are also the optimal agents for the treatment of peptic ulcer disease and prevention of complications of peptic ulcer disease in chronic users of NSAIDs.
The potency of PPIs makes them the agent of choice for a variety of patients. The drugs also have a long reputation for having a favorable side-effect profile.
Due to this combination of efficacy and safety, PPIs are among the most widely prescribed drugs in all of clinical medicine, trailing only antihypertensives and antidepressants in total number of prescriptions. This means that many of our postmenopausal patients are using these drugs. Those who are using a prescription-strength PPI should be aware of the potential risk of fracture, particularly if they are using it chronically. They also should be advised that exercise, calcium, and vitamin D are vital, as well as regular DEXA testing according to established guidelines.
Will nitroglycerin be the next treatment for osteoporosis?
Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA. 2011;305(8):800–807.
Khosla S. Is nitroglycerin a novel and inexpensive treatment for osteoporosis? JAMA. 2011;305(8):826–827.
Data suggesting that nitrates may protect against fracture date back to 2006, when Rejnmark and colleagues explored the use of these agents in 124,655 individuals who sustained a fracture and 373,963 age- and sex-matched controls.3 After adjustment for possible confounders, use of nitrates was associated with an 11% reduction in the risk of any fracture (OR, 0.89; 95% CI, 0.86–0.92) and a 15% reduction in the risk of hip fracture (OR, 0.85; 95% CI, 0.79–0.92).3
However, in 2009, Wimalawansa and colleagues found no benefit of transdermal nitroglycerin in preventing bone loss in early postmenopausal women.4 In their 3-year, randomized, double-blind, placebo-controlled trial, 186 postmenopausal women (mean age, 56 years) were randomized to receive nitroglycerin ointment (22.5 mg/d) or placebo. After 36 months of therapy, changes in BMD at multiple sites were comparable between groups. Due to the significant incidence of headache related to nitroglycerin treatment, adherence was suboptimal (estimated at approximately 70%), perhaps contributing to the negative findings.4
Enter this study by Jamal and associates, who performed a double-blind, randomized, placebo-controlled trial 24 months in duration. Participants were 243 women with a mean age of 62 years and a lumbar spine T-score between 0 and –2.0. They were randomized to 15 mg daily of 2% nitroglycerin ointment (applied to the upper outer arm at bedtime) or placebo.
At 2 years, women in the nitroglycerin group had a significant increase in BMD at the:
- lumbar spine, from 1.05 to 1.14 g/cm2, for a percentage change of 6.7% (P<0.001) (placebo group change: 1.06 to 1.08 g/cm2)
- total hip, from 0.92 to 0.97 g/cm2, for a percentage change of 6.2% (P<0.001) (placebo group change: 0.93 to 0.92 g/cm2)
- femoral neck, from 0.88 to 0.93 g/cm2, for a percentage change of 7% (P<0.001) (placebo group change: 0.87 to 0.86 g/cm2).
Nitroglycerin also increased bone-specific alkaline phosphatase by 34.8% and decreased urine N-telopeptide by 54% (P<0.001). Incidence of serious adverse events did not differ between nitroglycerin and placebo groups (5 [42.5%]).