Fragility Fractures: Pharmacologic Treatment
After covering an introduction to fragility fractures and nonpharmacologic treatment options, we will cover pharmacologic management options for when the provider deems this to be appropriate. Treatment is usually initiated after any hip or vertebral fractures, T-score of less than 2.5 at the femoral neck, total hip or lumbar spine by DXA scan, post-menopausal women or men age 50 or older with osteopenia (T-score -1.0 and -2.5) at the femoral neck, total hip or lumbar spine by DZA and a 10 year hip fracture probability of greater than 3% or a 10 year major osteoporosis-related fracture probability of greater than 20% based on FRAX score (1). The goal with treatment aims to increase bone mass and strength by inhibiting bone resorption or promoting bone formation. Management and choice of agent is dependent on many factors and each case should be individualized depending on past medical history and toleration of agents.
The most common class of agents used are oral bisphosphonates. These have been shown to be efficacious and are typically affordable. There is more long-term safety data for these compounds also. Most providers view these as first line pharmacologic therapy. Specifically, they bind to hydroxyapatite and are absorbed by bone, which inhibits osteoclastic bone resorption via several modalities: cytotoxic or metabolic injury of mature osteoclasts, inhibition of osteoclast attachment to bone, inhibition of osteoclast differentiation or recruitment, and interference with osteoclast structural features necessary for bone resorption (2).
There are two subclasses of bisphosphonates, with the most common being nitrogen containing bisphosphonates. These include alendronate, ibandronate, pamidronate, risedronate and zoledronate. The non-nitrogen containing bisphosphonates include tiludronate, clodronate and etidronate. There are many studies showing reduced risk of spine and hip fractures (3-11). Before initiating therapy, it is important for the provider to screen for and possibly treat certain comorbid conditions including hypocalcemia, vitamin D deficiency and renal impairment. These are typically evaluated by laboratory studies. Bisphosphonates should be avoided in patients with creatinine clearance less than 30 (1).
Image 1 and 2. Examples of a bisphosphonate and calcitonin nasal spray used for fragility fractures.
Alendronate (Fosamax), risedronate (Actonel) and ibandronate (Boniva) are oral agents typically taken either daily or once weekly. It is important to counsel patients on taking this first thing in the morning on an empty stomach with at least 8 oz. (240 mL) of water because they are poorly absorbed when taken by mouth. The patient should stand upright for 30-60 minutes and refrain from taking anything by mouth besides water. This is done to minimize gastrointestinal adverse events including Barrett’s esophagus, dyspepsia, esophagitis and esophageal varices. Reflux without esophagitis is a relative, but not absolute contraindication (1). The risk of osteonecrosis of the jaw is less than 1 in 100,000 for oral bisphosphonates (12). This risk was originally shown mostly in cancer patients receiving high dose IV bisphosphonate therapy (95%), but a small number were also on low dose therapy (13). More recent studies also question the true incidence while taking oral or low dose therapy for osteoporosis with one study having zero cases out of more than 17,000 patients (12,14).
If patients that have low tolerance, gastrointestinal disease or assimilation problems, infusions or IV bolus formulations are available. Zoledronic acid (Reclast) can be infused for at least 15 min once per year or ibandronate (Boniva) can be infused as a 15 to 30 second intravascular injection. Ibandronate (Boniva) is available in both an IV form and oral form and is used less often than other bisphosphonates, as it is not recommended to reduce nonvertebral or hip fracture risk. Zoledronic acid has a higher risk of causing hypocalcemia and increase in creatinine and these need to be monitored closely (1).
Bisphosphonates should be initiated four to six weeks after a fracture and should not be discontinued in patients who have suffered a fragility fracture for at least 5 years due to potential for delayed healing time. If you are caring for a postmenopausal woman who is re-assessed after 5 years and found to be low to moderate risk may be considered for a temporary discontinuation for up to 5 years. The reasons behind this discontinuation or “holiday” was formulated to an increased risk of atypical femur fractures and possibly jaw osteonecrosis with long term use of bisphosphonates, although these are very rare (15,12). It has also been shown that there are residual effects for years after therapy is stopped, which is unique among osteoporosis agents. The evidence for maintaining bone density during these periods of discontinuation is stronger with alendronate and zoledronic acid due to binding affinity (16). It is still recommended to check bone density every 3 to 5 years. If there is any significant change during this time, therapy should be re-initiated.
Cost is also a factor when initiating therapy. Alendronate is available in generic form and typically costs around 10 USD per 30 days. The brand name agents for alendrone (Fosamax), risendronate (Actonel) and oral ibandronate (Boniva) typically cost 30-150 USD per 30 days. Zoledronic acid (Reclast) typically costs around 1000-1200 USD and Boniva (IV form) costs 400-500 USD. Co-pays and coverage are also dependent on insurance plans.
Denosumab (Prolia) is a monocolonal antibody that binds to RANKL to inhibit osteoclast formation and activation, which stops the progression of bone erosion and loss. It has been shown to reduce spine and hip fractures (17) and also has an indication for osteoporosis in men. Denosumab is typically administered once by subcutaneous injection every 6 months. It is typically not used first-line, but is a very good option for patients that are intolerant to bisphosphonates or have a history of renal failure. The beneficial effects are not observed until about 1 month after therapy and lasts 4-6 months. It has also been shown that the effects reverse if a dose is missed. Hypocalcemia and vitamin D deficiency should be managed before initiation of therapy (18). During trials, there was no increased risk of jaw osteonecrosis, atrial fibrillation or symptomatic hypocalcemia. However, there was an increased risk of cellulitis and skin rash. One study also showed increased risk of infection and urinary tract infection in kidney transplant patients (19). A similar risk to atypical femur fractures was also seen and providers will need to have a high index of suspicion for these fractures. It is recommended to monitor or re-evaluate risk every 5 to 10 years while on this medication. Cost can also be an inhibiting factor and cost is generally around 700-900 USD per treatment.
Estrogen replacement is another treatment option because estrogen receptors play a role in osteoclast apoptosis with many studies showing increased in bone density at the lumbar spine and reduced bone turnover (20). Selective estrogen receptor modulators (SERMs) are non-steroidal synthetic drugs that act like estrogen, but without the adverse effects on the breast and endometrium. The most commonly used agents are raloxifene (Evista), lasofoxifene (Fablyn) and bazedoxifene (Duavee), which was recently FDA approved (21). They have been shown to reduce vertebral fractures in postmenopausal women, but there is limited data supporting decreased risk of non-vertebral fractures. These agents are also used in the prevention and treatment of breast cancer, but showed increased risk of stroke, thromboembolism, leg cramps and vasomotor symptoms or hot flashes (22). Cost for raloxifene is around 100 USD per 30 days and data on pricing was not available for the other two agents.
Other more traditional hormone therapies are occasionally used that include estradiol (Estrace), estropipate (Ogen) or conjugated estrogens (Premarin). Generic forms of these agents are made and typically cost less than 10 USD per 30 days. Like SERMs, traditional estrogen replacement is not typically first line due to increased risk of deep vein thrombosis (DVT), breast cancer, cardiac events, stroke and endometrial cancer. Because of this, medications should be administered at the lowest effective dose for a short time period. There was also one study that showed women that abruptly stopped hormone replacement therapy were at a greater risk of fragility fractures (23).
Figure 1. Algorithm for medical management (Eastell 2019)
Calcitonin is another agent used and inhibits bone resorption by inhibiting osteoblast activity. There are conflicting studies on calcitonin and this is also typically a second line therapy. Calcitonin was shown to increase lumbar spine bone mineral density and decrease markers of bone turnover, but did not prevent new vertebral, non-vertebral or hip fractures (24,25). Calcitonin is available in injectable and intranasal once (Miacalcin, Fortical) forms. The injectable form is used every other day and the intranasal form is used once daily. An increased risk of malignancy (4.1% vs 2.9%) has been reported in a recent meta-analysis of 21 studies, but the data was not sufficient to name a specific type (26). Cost is normally 75-120 USD per 30 days.
Teriparatide (Forteo) is a recombinant human parathyroid hormone. It is the only approved anabolic agent for the treatment of osteoporosis and it stimulates osteoblastic bone formation to improve bone quality and bone mass. (27) Teriparatide activates osteoblasts by binding PTH/PTHrP type 1 receptor, which directly stimulates bone formation on active remodeling sites and on previously inactive bone surfaces. This leads to a rise in biochemical markers of bone formation and causes an increase in bone mineral density in the lumbar spine and femoral neck (28). It is administered with a daily subcutaneous injection. The recommended treatment length is 18 to 24 months and long term data and safety is limited. Side effects that are common include leg cramps, nausea and dizziness. Patients with any history of skeletal malignancy, bone metastasis or hypercalcemia should not use teriparatide. It is common to initiate bisphosphonate therapy after 18 to 24 months if bone mineral density is not maintained or if the patient is still at risk despite bisphosphonate therapy. Cost is also a potential inhibiting factor with pricing around 900-1000 USD per 30 days.
In conclusion, pharmacologic treatment for is normally initiated after any hip or vertebral fracture. It may also be started for individuals after a fragility fracture if the T-score of less than 2.5 at the femoral neck, total hip or lumbar spine by DXA scan, post-menopausal women or men age 50 or older with osteopenia (T-score -1.0 and -2.5) at the femoral neck, total hip or lumbar spine by DXA and a 10 year hip fracture probability of greater than 3% or a 10 year major osteoporosis-related fracture probability of greater than 20% based on FRAX score. Pharmacologic therapy is ideally initiated 4-6 weeks after sustaining a fracture.Providers should evaluate for and treat any hypocalcemia, vitamin D deficiency or renal disorder before therapy. Bisphosphonates are the most common agent used due to more long term data and affordability and are available in oral and infusion form. Denosumab is a subcutaneous injection used every 6 months, has an indication for osteoporosis in men and is a good option for patients with intolerability to bisphosphonates or with renal failure. Selective estrogen receptor modulators (SERMs) and estrogen replacement therapy are second line for fragility fractures or osteoporosis due to side effect profile. Calcitonin has conflicting studies and is also second line. Teriparatide is a recombinant parathyroid agent that can be used for 18 to 24 months but bisphosphonates or additional treatment is usually needed. Decisions regarding therapy should be made on an individualized basis and availability, cost, local guidelines and patient values should be considered.
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