Bisphosphonates and Fracture Healing In Orthopaedic Fracture Patients

Margaret H. Lauerman, B.S.
Paul S. Issack, M.D., Ph.D.
Joseph M. Lane, M.D.

With the increase in mean population age, there has been a rise in the number of patients who develop osteoporosis and subsequent insufficiency fractures. Up to one half of all women and one third of all men will sustain fragility fractures in their lifetime1. The mechanism underlying this loss of bone toughness in patients with osteoporotic fractures is an abnormality of bone remodeling, with uncoupling of bone formation and bone resorption. When this highly regulated linkage is disrupted, the structural and material properties of bone diminish. An imbalance in bone formation and resorption, with excessive bone resorption, results in diminished bone mineral density and is seen in several pathologic conditions including: post-menopausal osteoporosis, prior steroid use2, fibrous dysplasia3, Pagets disease, bone metastases, and heterotopic ossification2.

Bisphosphonate drugs, such as alendronate and risedronate, have been used to restore the balance between bone resorption and bone formation. There is abundant evidence suggesting that bisphosphonates decrease bone resorption by inhibiting the function of osteoclasts2. However, the role of bisphosphonates in fracture healing is less clear. For the practicing orthopaedic surgeon, an understanding of the current evidence for the use of bisphosphonates in fracture healing is important for decreasing the risk of future insufficiency fractures1, as only 13% of patients are receiving sufficient treatment for their osteoporosis1, 4.

In conditions of osteoporosis (bone density z-score greater than 2.5 standard deviations below the mean on DEXA scanning) and other diseases in which there is excessive bone resorption as described, bisphosphonate therapy is instituted to prevent fractures. Several studies have confirmed that bisphosphonates may decrease the risk of sustaining an insufficiency fracture. The Fracture Intervention Trial, one of the largest trials to date to investigate the effects of bisphosphonates in preventing fractures5, 6, suggests that these agents may provide a protective effect. In 2027 women with low bone mineral density, treatment with alendronate reduced the rate of vertebral fractures by 50% without an increase in side effects6. In the presence of a vertebral fracture or known osteoporosis, Levis and colleagues noted a reduction in the rate of symptomatic fractures overall by 34% and symptomatic vertebral fractures by 63% in those receiving alendronate therapy5. A significant reduction in fracture rate was noted as early as six months with alendronate therapy compared to the control group, and was sustained over the four-year follow-up period5.

The use of bisphosphonate treatment to increase bone mineral density and prevent fractures suggests a role for these agents in augmenting fracture healing. However, little is known about the effects of bisphosphonates specifically on fracture healing, rather than bone density augmentation. Because of the increasing use of bisphosphonates to improve bone density in postmenopausal osteoporosis, physicians are now encountering a large number of patients with fractures who have received bisphosphonate treatment prior to their fractures. The effects of this prior treatment on bone remodeling and fracture healing, as well as the role of bisphosphonate therapy overall, are beginning to be understood (Table 1). Callus size may increase with pre-fracture treatment, although this is confounded by post-fracture treatment with bisphosphonates in many animal experiments7-10. The literature also suggests that bisphosphonate treatment prior to sustaining a fracture does not decrease fracture density or strength, but it is unclear whether mechanical properties are improved9-11. Bisphosphonates may be uniquely helpful in osteonecrosis patients, where this pharmacological augmentation allows for maintenance of intrinsic osseous architecture12. Long-term therapy only increased callus size; other variables remained unaffected9.

Should bisphosphonate therapy be continued after sustaining a fracture? Although physicians are increasingly prescribing bisphosphonates to osteoporotic patients after fractures to decrease future fracture risk and lessen fracture site osteopenia, the effects of this treatment on bone remodeling and healing are poorly understood. Post-fracture bisphosphonates increase callus size7, 11, 13; however this increase in size is not necessarily reflective of increased quality. It remains unclear exactly how bisphosphonate post-fracture treatment affects fracture strength, with the literature split on increasing strength and lacking effect7, 8, 10, 11, 13, 14. In ovariectomized rats, alendronate markedly reduced fracture healing rates and resulted in fracture callus consisting of poor quality, mainly woven, bone15. In clinical trials, use of bisphosphonate post-fracture treatment for both distal forearm fractures and fractures of the lower extremity in osteoporotic women allowed for maintenance of fracture site bone mineral density16-18 (Table 2).

The major adverse reaction to bisphosphonates is gastrointestinal, with patients often complaining of nausea, vomiting or abdominal pain2. To minimize this problem, patients should remain upright for 30 minutes after administration. Bisphosphonates may also cause hypocalcemia and hypophosphatemia. They are contraindicated in patients with renal failure or preexisting hypocalcemia2.

Teriparatide, the active N-terminal fragment of parathyroid hormone (PTH) (residues 1-34) is used for the treatment of post-menopausal women with osteoporosis who are at high risk for fracture19. Specifically in ovariectomized animals, PTH can reverse osteopenia induced by the estrogen withdrawal20, and in fracture models, when administered in intermittent doses, PTH increased bone density, fracture strength and bone quality21-23. PTH stimulates osteoblast differentiation, which in theory should complement the increases in bone density seen with bisphosphonate treatment. Bisphosphonates have been noted to maintain increases in bone density after PTH administration24, 25. However, combination therapy is less effective than PTH treatment alone, suggesting that bisphosphonates antagonize the anabolic effects of PTH on osteoblasts6, 26.

There is no current evidence that pre-fracture bisphosphonates, when not contraindicated by renal failure or gastrointestinal side effects, harm fracture strength14 or other healing parameters. This, combined with the clearly significant reduction in fracture rates in osteoporotic patients, suggests that bisphosphonates are an appropriate treatment for the osteoporotic patient. However, administration of bisphosphonates immediately post-fracture may still impair fracture healing, and further studies aimed at this question will provide an optimal treatment algorithm for bisphosphonate use in the fractured osteoporotic patient.

Study

Treatment Time

Animal

Drug Given

Callus Size/BMD Enhancement

Osseous Healing Change

Amanat N, 2005

Post-Fracture

Rat

Pamidronate

Yes

Not Measured

Koivukangas A, 2003

Both

Rat

Clodronate

(Long-Term)

Yes

No

Cao Y, 2002

Post-Fracture

Rat

Alendronate

Yes

Decreased with Treatment

Li C, 2001

Both

Rat

Incadronate

Yes

Decreased with Treatment

Madsen J, 1998

Both

Rat

Clodronate

Yes

Not Measured

Peter C 1996

Both

Dog

Alendronate

Yes

No

Goodship A, 1994

Both

Sheep

Pamidronate

Yes

Decreased with Treatment

Table 1. Animal Studies for Fracture Healing with Bisphosphonate Use.

Study

Drug

Injury

Patient Number

Effect on Fracture Healing

Van der Poest Clement E, 2002

Alendronate (Post-Fracture)

Lower Leg Fracture

41

Maintains Bone Mineral Density

Van der Poest Clement E, 2000

Alendronate (Post-Fracture)

Colles Fracture

37

Maintains Bone Mineral Density

Adolphson P, 2000

Clodronate (Post-Fracture)

Colles Fracture

32

Increased Bone Mineral Density

Table 2. Human Clinical Trials for Fracture Healing with Bisphosphonate Use.


References

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