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.
References
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