Monday, January 5, 2015

The Impact of Bisphosphonates on Bone Health

     There are 44 million Americans living with osteoporosis or low bone density, with roughly one in two women and one in four men over age fifty sustaining fractures as a result of poor bone health (National Osteoporosis Foundation, n.d., p.6).   Estimates suggest that 10 million people already have osteoporosis and another 34 million are suspected to have undiagnosed low bone density, further adding to the emotional and fiscal impact of bone disease across the nation (p. 8).  According to the National Osteoporosis Foundation (NOF), osteoporosis accounts for more than 2 million fractures in 2005, a cost of $19 billion, with numbers forecast to exceed 3 million fractures, at a cost of $25.3 billion by 2025 (p. 8).  They estimate 300,000 hip fractures are occurring yearly, with 25% of these injured patients over age fifty dying within a year of fracture (p. 8).  Reports also suggest that post-menopausal women are vulnerable to osteoporosis and fractures, losing up to twenty percent of their bone mass within five to seven years following cessation of menses (p. 4).

      Bisphosphonate (BP) agents, previously known as disphosphonates, were first synthesized in the late 1800’s, expanding research towards fluoride’s impact on tooth enamel and calcium chelation of dental plaque in the mid 1960’s, finally culminating as research on the treatment of bone diseases in the late 1960’s (Francis & Valent, 2007, pp. 2-3).  These authors found that international sharing of physical-chemical research on bisphosphonates (BPs) helped to reveal possibilities for reducing bone resorption by blocking the dissolution of hydroxyapaptite crystals (p. 4). 
     Drake, Clarke and Khosla (2008) found BP agents are structurally similar to the naturally occurring inorganic pyrophosphate (PPi), both demonstrating efficacy in regulating bone mineralization through its binding action on hydoxyapaptite crystals (p. 1033).  Besides BP’s attraction to bone minerals, they also integrate themselves directly into active areas of bone remodeling and employ bone-specific targeting with the excess excreted through the renal system (p.1033).  However, these authors state there’s limited bioavailability of oral BP, with poor absorption by the gastrointestinal (GI) tract and approximately fifty percent selectively absorbed by skeletal tissues with overall absorption correlating with favorability of host conditions (p. 1035).  According to Vigorita, Silver and Eisemon (2012), possible adverse issues with BP’s bone mineral regulation has prompted the Food and Drug Administration (FDA) to warn health professionals about unusual femoral fractures reported with long term use (p. 861). 

        Francis et al. (2007, p. 5) found that etidronate (Didronel), an early first-generation drug with an additional use as a hypocalemic, had its first human trial as a germinal bisphosphonate in 1967 for treatment of heterotrophic calcifications in chest musculature caused by myositis ossificans progressiva (MOP).  The study found it blocked advancement of calcifications and decreased inflammatory ectopic lesions following the third oral treatment, with the disease being managed by occasional oral treatments over her lifetime (p. 5).  Ciccone (2013) found that etidronate, known as a bone resorption inhibitor, decreases bone resorption or bone turnover by blocking calcium hydroxyapatite crystals via a binding mechanism with calcium phosphate (p. 406).  He also reports this drug has usefulness in combination with other agents for the management of hypercalcemia found with malignancies (p. 406). 

     First generation non-nitrogen-containing BPs like etidronate had been difficult to safely administer for home use due to daily oral dosing and an upright posture for thirty minutes, refraining from eating for two hours prior or thirty minutes post meal to keep GI effects to a minimum (Drake et al, 2008, p. 1035).  Other adverse reactions include impaired or a metallic taste, rash, muscular aches, kidney toxicity and necrosis of the jaw, with contraindications in the presence of severe renal impairment (creatinine >5mg/dL) or hypercalcemia due to hyperparathyroid disease with caution advised in pediatrics, pregnancy, lactating mothers, long bone fractures, low vitamin D or creatinine levels of 2.5-4.9 mg/dL (Ciccone, 2013, pp. 406-407). Decreased absorption occurs with concurrent use of buffering agents containing aluminum, calcium, iron and magnesium, as well as, antacids and mineral supplements, although calcitonin may potentiate its effect (p. 407). Similarly, foods containing aluminum, calcium, iron and magnesium may impair drug absorption (p. 407).

     Tiludronate (Skelid), another non-nitrogen-containing BP drug, also structurally similar to the PPi, gets integrated into molecules of new adenosine triphosphate (ATP), creating an intracellular cytotoxicity and eventual osteoclast apoptosis (Drake et al, 2008, p. 1034).  According to Ciccone (2013), tiludronate is taken orally for three months and used in the management of Paget’s disease when the serum alkaline phosphatase > 2 times upper normal level (p. 1079).  The adverse reactions include vertigo, anxiety, fatigue, bronchitis, chest pain, dependent edema, GI issues, pathologic fractures, paresthesia and infection, as well as, jaw necrosis, musculoskeletal pain, rash and spasms (p. 1079). Contraindications include hypersensitivity, severe renal impairment, with caution used in the presence of dental surgery, pediatrics, pregnancy and lactation (p. 180).  Drug to drug interactions causing decreased absorption are aspirin, antacids containing aluminum or magnesium and calcium supplements, but this drug’s impact may be potentiated by indomethacin (p. 1080).   Drug to food interactions occur with all foods and results in decreased drug absorption (p. 1080).

     The newer second- and third-generation BPs, also considered bone resorption inhibitors, have nitrogen-containing side chains that inhibit the enzyme farnesyl pyrophosphate (FPP), in turn minimizing resorption through the disruption of a protein signaling pathway necessary for osteoclast activity on the bone (Vigorita et al, 2012, p. 864).  According to Capsoni, Longhi and Weinstein (2006), nitrogen-bisphosphonates (N-BPs), known as aminobisphosphonates, are more potent and more selective than early BPs and include alendronate (Fosamax), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel) and zoledronate (Reclast) (p. 219).  Alendronate, ibandronate and risedronate are first line therapies for the treatment and prevention of osteoporosis, while pamidronate and zolendronate are important agents in minimizing bone complications and managing severe hypercalcemia associated with multiple myeloma or bone metastases from prostate or breast cancer (p. 219).   Drake et al. (2009) found that BP’s long skeletal half-life, up to eight years with pamidronate, warrants great caution during consideration for use in adolescents, pre-pubescent girls and in fetal development (p. 1041).

     Ibandronate is typically used for postmenopausal treatment or prevention of osteoporosis, being orally administered once a month or through the quicker acting intravenous (IV) method every three months (Ciccone, 2013, p. 531).  According to Drake et al. (2008) ibandronate’s efficacy is best for use with spinal fractures, while alendronate and risedronate have more effectiveness in prevention and treatment of spinal and hip fractures, loss of height and spinal deformities (p. 1036).   According to Vitor, Nunes, Fonseca and Freitas (2012), N-BPs were created to improve patient tolerance, enabling longer intervals between doses and less adverse reactions (p. 342).  Although these newer N-BPs have demonstrated a short term record of less adverse GI issues, studies suggest that long term use may still result in upper GI issues similar to those seen with the early, non-nitrogen containing BPs ( p.342).  

     The typical side effects for ibandronate and most BP’s includes mild GI issues and musculoskeletal aches and pains (Ciccone, 2013, p.531).  According to Capsoni et al. (2006), jaw necrosis can also be an issue with long term BP use, characterized by bone tissue not healing or slowly healing following mild dental trauma or tooth procedures (p. 219).  In a study of infusion administered BP therapy for myeloma and breast cancer patients, osteonecrosis of the jaw had a 10% incidence with zoledronate, 4% with pamidronate, .7% with alendronate, but insignificant findings presented with ibandronate and risendronate as too few cases were involved in the study (p. 220). However, these authors feel strongly that a direct correlation exists between BP therapy and osteonecrosis of the mandible or maxilla (p. 221).  

     According to Goossens, Spahr and Rubbia-Brandt (2013), they found only eight cases of documented BP hepatotoxicity, with none involving ibandronate, until their case report demonstrated an acute drug-induced cytolytic hepatitis related to ibandronate treatment for osteoporosis (p. 1139-41).  In light of risks associated with BP therapies, a study by Ro and Cooper (2014) presented safety considerations through proposed drug holidays or drug cessation based on factors relating to the antiresorptive potency and binding affinity of each BP and associated side chains (p. 48).  Zoledronate with the highest antiresorptive potency is followed by risdronate, ibandronate and alendronate (p. 48).  The highest binding affinity occurred with Zoledronate, decreasing to alendronate, ibandronate and risedronate, respectively (p. 49).  Proposed interventional algorithms for determining appropriateness of drug holidays are based on fracture risk, duration of BP treatment, type of BP used and patient compliance as a means to provide an evidence based hiatus from BP therapy for one to five years (p. 50).

     In a report by Tandon, Sharma and Mahajan (2014), their analysis studied proposals for and against drug holidays, finding that evidence provided only weak support for the concept of drug holidays (p. 112).  While they applauded the theoretical value of an alternative option that would decrease BP risks, the benefit of this discontinuation was not clearly substantiated by clinical findings and warrants further research (p. 113).  They did find recommendations from the American Society for Bone and Mineral Research stating long term use of BPs, in excess of five years, or drug holidays in excess of five years warranted an annual assessment by clinicians, evaluating issues such as medical history and bone density (p. 113). Vigorita et al. (2012) suggested that although osteoporosis treatment may be effective, the long term impact of N-BP’s anti-osteoclastic activity may actually be creating abnormal bone remodeling and observable changes in osteoclast morphology, referred to as “giant osteoclasts”, increasing a vulnerability for adverse skeletal issues or fracture (p. 864).  Drake et al. (2009) went on further to suggest that prolonged BP therapy can actually create “frozen bone” through the over-suppression of osteoclast activity, impairing the body’s innate ability to repair fractures (p. 1042).

     Oral treatment with N-BP’s may typically consist of once weekly dosing for aldendronate and risdronate or monthly dosing for ibandronate or risedronate, but a varied schedule of  IV or infusion administration for ibandronate, pamidronate and zoledronic acid (Drake et al., 2009, p. 1035).  According to Ciccone (2013), zoledronic acid ( Reclast)  may be administered yearly, has drug interactions with loop diuretics and aminoglycosides, and requires caution with severe renal impairment and history of aspirin induced asthma (p. 1176).  Some additional adverse effects for this specific N-BP include agitation, anxiety, conjunctivitis, decreased blood pressure, gastrointestinal issues, renal failure, rash, anemia and low blood levels of calcium, magnesium, potassium and phosphorus (p. 1175).  Additionally, it is believed that 10% to 30% of patients receiving an initial N-BP infusion or IV will experience an acute reaction of flu-like symptoms such as myalgia, low grade fever, headache and body aches. 
     It is clear that BPs can be highly effective in the treatment of bone health, with inherited skeletal disorders such as osteogenic imperfecta (OI) in children being effectively treated with oral alendronate to decrease the incidence of fracture, thus limiting medical costs and personal suffering (Drake et al., 2009, p. 1040).  BPs can also assist in glucocorticoid-inducedosteoporosis as seen in rheumatic conditions and can reduce osteolytic bone pain, as well as, bone metastases in breast cancer through IV administration of pamidronate, zoledronic acid or ibandronate (p. 1039).  However, studies regarding BP therapy for the prevention or treatment of osteoporosis suggest focusing use on patients at high risk for osteoporotic fractures, carefully avoiding long term BP prescriptions as a way to limit abnormal bone modelling and lower fracture risk (Lee, Lee, Moon & Lee, 2014, p. 56).

     Physical therapists must be cognizant of the prescribed BP, the drug or food interactions and side effects associated with the specific bone resorption inhibitor.  Pain, flu-like symptoms and gastrointestinal issues are noted side effects and must be recognized early.  Careful program planning is necessary to minimize fall risks and cardiopulmonary challenge, while increasing the regenerative weight bearing forces on the spine and peripheral joints.  Monitoring blood pressure, heart rate and auscultation is appropriate, being provided as clinically indicated.

     In closing, the studies in this paper highlight the necessity for judicious use of all BP therapies for bone health, utilizing strong clinical judgment, comprehensive patient education and interventional algorithms to help determine the risk to benefit analysis.  Capsoni et al. (2006) state long term BP use is risky and the casual consideration for systemic or local predispositions, such as pending dental work, increases medical risks of osteonecrosis of the jaw and causes unnecessary suffering (p. 220).  Clearly, more research is needed to explore the best treatment duration and appropriate selection of drug candidates for the best outcomes with bone health.
Capsoni, F., Longhi, M. & Weinstein¸R. (2006). Bisphosphonate-associated osteonecrosis of the jaw: The rheumatologist’s role.   Arthritis Research & Therapy, 8(5), 219-224.          doi:10.1186/ar2050  
Ciccone, C. D. (2013). Drug guide for rehabilitation professionals. Philadelphia, PA: F. A.  Davis Company.
Drake, M. T., Clarke, B. L. & Khosla, S. (2008). Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin Proc, 83(9), 1032–1045. Retrieved from  
Francis, M. D. & Valent, D. J. (2007). Historical perspectives on the clinical development of         bisphosphonates in the treatment of bone diseases. J Musculoskelet Neuronal Interact, 7(1), 2-8.  Retrieved from
Goossens, N., Spahr, L. & Rubbia-Brandt, L. (2013). Severe immune-mediated drug-induced liver injury linked to ibandronate: A care report. Journal of Hepatology, 59, 1139-1142.  doi:
Lee, J. H., Lee, Y.-H., Moon, S.-H., &  Lee, Y.-S. (2013). Influence of insurance benefit criteria on the administration rate of osteoporosis drugs in postmenopausal females. Clinics in Orthopedic Surgery, 6, 56-61.    
National Osteoporosis Foundation (n.d.).  Strong voices for strong bones.  Advocacy Tool Kit, 1-49.  Retrieved from   
Ro, C. & Cooper, O. (2013). Bisphosphonate drug holiday: Choosing appropriate candidates.  Curr Osteoporos Rep, 11(1), 45-51.  doi:10.1007/s11914-012-0129-9
Tandon, V. R., Sharma, S. & Mahajan, A. (2014). Bisphosphonate drug holidays: Can we recommend currently? Journal of Mid-Life Health, 5(3), 111-114.  doi: 10. 4103/0976-7800.141186
Vigorita, V. J. V., Silver, J. S. & Eisemon, E. O. E. (2012). Osteoclast abnormalities in fractured bone during bisphosphonate treatment for osteoporosis: A case report. Skeletal Radiol, 41,861-865. doi:10.1007/s00256-012-1407-4
Vitor, S. Nunes, A., Fonseca, C. & Freitas, J. (2012). Ibandronate-associated ischemic colitis--case report. ACTA REUMATOL PORT., 37,342-344.  Retrieved from

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