The downside to bisphosphonates

The major limitation to bisphosphonate use in the last few years has been concern over ONJ, not esophageal erosion or ulceration, as originally feared. The weekly or monthly dosing schedules now utilized limit esophageal contact with these acids. Therefore, most upper GI complaints in patients taking bisphosphonates are actually related to gastroesophageal reflux disease (GERD), a problem in 35% of patients. For those who cannot differentiate between their own GERD and tablet intolerance, a liquid formulation of alendronate is available. IV ibandronate is also an option at 3 mg every three months.

ONJ has occurred in one in 100,000 individuals on oral bisphosphonates, while 95% of cases are related to IV bisphosphonate use. Sixty percent of those with ONJ had a recent dental extraction as a predisposing factor, and in the majority, an underlying malignancy was an added risk. In this latter group, the incidence of ONJ rises to nearly 2%, especially in those with breast cancer or myeloma.

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Prudent care suggests that patients starting bisphosphonates complete all invasive dental procedures first. Patients needing such procedures during bisphosphonate therapy are usually instructed to stop the bisphosphonate for two months prior to an implant or an extraction. It is advisable to allow healing to occur and resume therapy two months later. Teeth cleaning, fillings, or crowns do not appear to pose a risk to patients on bisphosphonates and may in fact limit the need for future extractions, preserving therapy.

What else besides bisphosphonates?

Recognition that 52% of women receiving bisphosphonate therapy have vitamin D levels <30 ng/mL has led the trend toward higher vitamin D dosing. Bisphosphonate patients, as well as others considering such therapy but preferring to try calcium, vitamin D, and exercise regimens first, will benefit from higher daily administration of vitamin D3. Fosamax is now available with 2,800 or 5,600 units of D3 in the weekly tablets.

Low vitamin D serum levels were identified at all latitudes in the United States, suggesting that sun avoidance is common in the osteoporotic population and that oral dosing recommendations of 400 IU are inadequate. Recent data also identify gains in proximal muscle strength and reductions in falls as a potential benefit of vitamin D supplementation. A meta-analysis of vitamin D studies showed a 20% reduction in rates of falling compared with calcium or placebo.3 Capsules containing 1,000 units of vitamin D3 are inexpensive and readily available OTC, simplifying present calcium and vitamin D recommendations for patients. The increasing use of proton-pump inhibitors, which may impair calcium carbonate absorption, also argues for calcium citrate utilization in those individuals on acid-suppressing regimens.

Another challenge to bisphosphonate pre-eminence and osteoporosis therapy is the increasing use of teriparatide (Forteo), an anabolic agent working through the parathyroid hormone receptor in bone to increase bone remodeling. The result is bone formation that exceeds bone resorption, yielding increased skeletal mass and bone strength. Prior resistance to use of this agent was due to cost, $8,000 yearly, now lessened by a partial Medicare Part D coverage schedule. Daily injection fears are mitigated by a simple injector pen and local classes supervised by teaching nurses. Bisphosphonates need to be discontinued when teriparatide is initiated to maximize benefit of the latter. Teriparatide therapy typically lasts two years, after which bisphosphonates are resumed to maintain the BMD gains, which exceed 12% in the lumbar spine. New vertebral-fracture risk reduction reaches 65%, and nonvertebral-fracture risk reduction is 53%. Dosing is 20 µg subcutaneously, with needle change (31 gauge, 8 mm) after each use.

Not for women only

In this update, I have focused on women, with most literature data related to them and osteoporosis, traditionally a “woman’s” disease. However, one in five fractures occurs in men, and their mortality after hip fracture exceeds that in women by a factor of two. Similar, albeit less profound, associations are noted with other major osteoporotic fractures in men.

The diagnostic assessment in men needs to be more detailed than for women, since more than 50% of men have secondary osteoporosis. That is, an identifiable disorder contributes to their disease. The most common cause is testosterone deficiency; levels <300 ng/mL are considered treatable. Look for androgen-ablative therapies for prostate cancer as provocative of bone loss and narcotic administration with secondary lowering of testosterone as an additive factor. Excessive glucocorticoid usage or alcohol intake are the next two important risk factors in men. Height loss >2 inches is a clue toward the diagnosis, since vertebral fracture may be clinically silent in more than two thirds of cases. The newer DEXA scanners have a vertebral-fracture assessment arm, which aids in the identification of these often silent back fractures leading to height loss. This added test must be requested, as it cannot be added by the testing lab on its own.

Men at high risk, with T scores <-2.5, may be treated with androgens or bisphosphonates or both. Bisphosphonates are considered first-line treatment. Low BMD in men predicts an increased fracture risk similar to that seen in women, but be aware that lumbar BMD is often falsely elevated in men due to the presence of osteoarthritic spurs and vascular calcifications. Femoral neck or total femur scores are thus the more important values to consider. Androgen replacement will increase BMD in hypogonadal men and has the added potential to improve mood and strength, diminishing the risk of falls.

These benefits need to be considered along with the potential risks of prostatic growth, including cancer. Alendronate provides BMD increases in men similar to those seen in women, independent of baseline testosterone levels, and does so as well in men on concurrent androgen replacement. Risedronate has similar effects in men with primary and secondary osteoporosis, including men on glucocorticoids. There are limited data on the use of nasal calcitonin in men, but its low antiresorptive ability makes it a usual last choice for both men and women. Teriparatide is approved for men with idiopathic or hypogonadal osteoporosis.

Don’t wait to treat

New agents are on the horizon, including strontium and denosumab, but we have excellent medications now. The major problem is not availability of drugs, but identifying patients and treating with the agents we have. Three out of four women do not receive treatment during the year following an osteoporotic fracture, and presently one in five women over the age of 50 has at least one vertebral fracture. We need to improve these statistics dramatically.

Dr. Waxman is clinical professor of medicine, University of California, San Francisco, and staff rheumatologist, Northern California Medical Associates in Santa Rosa.


  1. Bone HG, Hosking D, Devogelaer JP, et al, for the Alendronate Phase III Osteoporosis Treatment Study Group. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199.
  2. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res. 2005;20:141-151.
  3. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA. 2004;291:1999-2006.