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Good news, bad news for osteoporosis
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The current issue of The New England Journal of Medicine reports the anti-fracture effectiveness of denosumab, a monoclonal antibody against RANK ligand (RANKL) that inhibits the action of osteoclasts — the cells responsible for bone resorption. Researchers of the first article studied men with prostate cancer receiving androgen deprivation therapy, while researchers of the second article studied women with postmenopausal osteoporosis. The drug has been under development by Amgen for some time, and each new publication adds more to our understanding of the pathogenesis and management of osteoporosis.
With the exception of teriparatide, the available therapies for osteoporosis also act by inhibiting the action of osteoclasts. Estrogen and estrogen agonists/antagonists (formerly known as selective estrogen receptor modulators or SERMs) also interfere with the RANK, RANKL and osteoprotegerin (OPG) system, while the bisphosphonates (the most widely prescribed osteoporosis therapies) have a more direct action on the osteoclast that does not appear to involve the same system. Teriparatide directly stimulates osteoblasts to promote bone formation.
Raloxifene (Evista, Eli Lilly) is available as a daily oral preparation while estrogen is available as an oral or transdermal product. The bisphosphonates are available as daily, weekly or monthly tablets and as quarterly or annual IV preparation. Teriparatide is given as a daily subcutaneous injection.
In sharp contrast, denosumab, if approved by the FDA — which seems likely based on the large body of positive preclinical and clinical data — would be available as a subcutaneous injection given once every six months. The assumption is that this will markedly improve patient adherence to therapy. I have no idea how this drug would be available for patient use, but my hope is that it would be administered every six months by a health care provider and not the patient. For most patients who need therapy to minimize the risk of osteoporosis-related fractures, a semi-annual visit to their doctor would be an ideal pattern to make sure that the patient is paying attention to the non-pharmacologic aspects of osteoporosis management — nutrition, exercise and fall prevention.
Ibandronate (Boniva, Roche Laboratories and GlaxoSmithKline) is available as an IV injection every three months, and zoledronic acid (Reclast, Novartis) is available as an annual IV infusion. I have not recently checked on this, but I presume that this too improves compliance with therapy. The difference is that most often these drugs are given at an infusion center where cancer and not osteoporosis is appropriately the major concern. It seems less likely that the critical non-pharmacologic aspects of skeletal health would be addressed at these visits.
Now the “bad” news — at least from my perspective.
The previous issue of the NEJM carried the results of two controlled clinical trials of vertebroplasty for the relief of pain associated with vertebral fractures in osteoporosis. Both trials reported the disappointing news that the procedure was no more effective in reducing the acute and chronic back pain associated with these fractures.
There are many reasons to be disappointed with these findings. Most review articles on osteoporosis focus on hip fracture as being the most devastating osteoporosis-related fracture. To be sure, a hip fracture results in a dramatically high mortality and major morbidity for those who survive and is a very costly medical condition. In contrast, spine fractures do not receive the same attention in the literature and are all too often overlooked. Many vertebral fractures are asymptomatic, so-called subclinical fractures. They are often detected when lumbar spine bone density is measured by DXA or in those centers where vertebral fracture assessment is part of the routine DXA study. All too often, when such fractures present on chest or abdomen X-rays taken for reasons other than assessing the spine, the radiologist report makes no mention of them. That is simply inadequate because these fractures are very strong predictors of subsequent hip fracture and all such patients should be treated for osteoporosis once other causes for fracture have been excluded.
What bothers me most is that vertebral fractures tend to occur in patients a decade or so younger than those experiencing a hip fracture. They result in substantial morbidity, without mortality, that interferes with the activities of daily living for possibly decades. These fractures need as much attention as the hip fracture, if not more. The altered body image associated with the “Dowager’s hump,” the chronic back pain, the inability to do all the things you could do before the fracture make life miserable for far too many.
The vertebroplasty is designed to minimize the altered body habitus of the spine fracture patient, and intuitively I would have expected the clinical trials to confirm that. Two controlled clinical trials with a negative outcome cannot be ignored, but we really need to analyze why this is the case. There is no doubt that the patients with symptomatic vertebral fractures have ongoing morbidity, but the data suggest that it may not be related to the altered anatomy.
In my clinic practice, I see many more patients with vertebral fractures than hip fractures, and they are referred because they hurt. For most of them, the fracture is too old for vertebroplasty to be an option and the emphasis on management has to be an effective rehabilitation program, as well as therapy for osteoporosis to minimize the risk of future fractures. Over the years, I have referred almost every one of these patients to colleagues in rehabilitation medicine and will continue to do so. The long-term outcomes remain disappointing, and the seeming failure of vertebroplasty (I am not yet convinced we have seen the final chapter on that procedure) is a blow.
The take home message! Prevent even the first fracture if at all possible. We have the tools to determine which patients are at greatest risk for fracture. We have several therapies with proven anti-fracture effectiveness and more on the way. No matter if your practice is primary or subspecialty care, your professional organization has most likely developed clinical practice guidelines which, if followed, should make a major impact on your patient’s risk of long-term morbidity from a preventable fracture.
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