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Bisphosphonates

Inhibitors of osteoclast mediated bone resorption.

Bisphosphonates have a role in the management of osteoporosis, hypercalcemia of malignancy, and bone metastases from solid tumors and multiple myeloma.

These agents have been used for premenopausal patients with bone loss from premature ovarian failure due to chemotherapy and in postmenopausal patients treated with aromatase inhibitors.

Classified as anti-resorptive agents with a very high affinity for bone mineral and bind to hydroxyapatite crystals on bony services, where they inhibit osteoclast mediated bone resorption.

They bind with high affinity to bone minerals such as calcium and reduce osteoclast mediated bone resorption.

Bisphosphonates are analogues of pyrophosphate that concentrate in active bone remodelling sites. 

 

PDuring bone resorption, active osteoclasts ingest the bisphosphonate by endocytosis and undergo cell death. 

Potency measured by ability to inhibit the enzyme farnesyl diphosphate synthase in osteoclasts (Dunford JE et al).

Taken up by osteoclasts and cause cell death, therby reducing bone degradation.

Non-nitrogen-containing bisphosphonates ( clodronate) act through cytotoxic effects on osteoclasts whereas nitrogen-containing bisphosphonates ( pamidronate, ibandronate and zoledronate) have a direct apoptotic effect.

Decrease risk of skeletal complications and pain associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma.

Bisphosphonates work by interrupting the recruitment, maturation, and attachment of osteoclasts, and induce apoptosis in osteoclasts and plasma cells.

Zoledronic acid is the only bisphosphonate shown to confer a survival advantage in myeloma.

May induce hypocalcemia in patients with a vitamin D3 deficiency.

Associated with renal failure and pamidronate (Aredia) and zolendronic (Zometa) acid are associated with osteonecrosis of the jaw.

Premature discontinuation rate may exceed 50% at 1 year (Weycker D, Cramer JA).

Risk factors for premature discontinuation of bisphosphonates include age, dosing schedule, associated polypharmacy, and adverse drug reactions.

Bisphosphonates reside in bone for a long period of time, and continue to have effects on bone even after they are discontinued.

 

Bisphosphonates may also have antitumour and/or antiangiogenic effects, although the clinical relevance of these preclinical observations is controversial.

Mechanism of renal toxicity poorly understood.

Caution advised when using these agents with aminoglycosides, loop diuretics and other nephrotoxic drugs.

Analogues of inorganic pyrophosphates with low intestinal absorption.

Esophagitis associated with oral bisphosphonates, usually when not taken appropriately.

Bisphosphonates are associated with esophagitis and esophageal/gastric ulcers so the instructions for ingestion must be followed carefully to avoid side effects. 

Oral bisphoshonates can cause serious esophagitis and crystalline deposits of bisphosphonates may remain in the esophagus (Ribeiro A).

Between 1995 and 2008 23 cases of esophageal cancer was reported to have occurred in patients using the bisphosphonate alendronate (FDA).

Among patients in the UK General Practice Research Database with a mean follow-up time of approximately and 4.5 years and involving 41,826 individuals with 81% female patients the use of oral bisphosphonates was not significantly associated with esophageal or gastric cancer (Cardwell CR).

Excreted through the kidneys without alteration and have a high affinity for hydroxyapatite crystals.

Half life in bones measured in years.

Most bisphosphonates have a half-life that exceeds 10 years, and may be associated with long-lasting inhibition of bone modeling afecting healing of physiologic microcracks causing clinically apparent stress fracturesin areas with high mechanical stress.

Estimated half life for alendronate is up to 12 years.

The risk of nephrotoxicity must be assessed individually for each biphosphonate for each clinical situation.

Reduces bone turnover, increases bone density, and reduces fracture risk in multiple clinical trials.

Mechanism of action targets the osteoclasts and therefore decreases bone resorption and also bone formation.

Bone resorption decreases initially and is followed within weeks to months by decreased bone formation.

Serum C-telopeptde, a collagen cross-link protein release when bone is resorbed, and osteocalcin, a protein product of osteoblasts that reflects bone turnover including bone formation.

Include alendronate (Fosamax), risendronate (Actonel), zoledronic acid (Zometa), pamidronate (Aredia)and ibandroate (Boniva).

Alendronate or risendronate Is the treatment of choice for most patients initiating oral bisphosphonates.

Contraindications to the use of oral bisphosphonates include achalasia, esophageal stricture, and Barrett’s esophagus.

Patients with G.I. contraindications or poor adherence to oral medications are candidates for intravenous zoledronate.

Alendronate, risendronate, pamidronate, zoledronic acid, and ibandronate have higher potency due to their nitrogen side chain and are referred to associated aminobisphosphonates.

Pamidronate 90 mg intravenous monthly compared to placebo in 392 stage III patients with myeloma revealed fewer skeletal events 24% vs. 41%, with a longer time to the first skeletal event, with a longer time to the first pathologic fracture and first radiation therapy, with a lowered rate of hypercalcemia, less osseous pain, and a superior quality of life.

Nitrogen containing agents include zoledronic acid, pamidronate, alendronate, risendronate and ibandronate.

The nitrogen moiety in bisphosphonates render these drugs more potent as inhibitors of bone resorption than non nitrogen containing bisphosphonates etidronate (Didronel) and clodronate .

In patients with pre-existing chronic kidney disease or with other risk factors for renal function impairment such associated myeloma, diabetes, hypertension, or advanced age, intravenous administration of bisphosphonates must the be carried out with caution.

Bisphosphonatts may accumulate in patients with impaired Kidney function and as such oral or IV bisphosphonates are not recommended with a creatinine clearance of less than 30-35 mL per minute.

Correction of hypocalcemia and vitamin D deficiency is necessary prior to bisphosphonate administration.

Increase bone mineral mass about 1% per year for up to 8-10 years.

For most agents 40-60% of bisphosphonates reaching the circulation are rapidly bound to bone explaining why the total plasma clearance is higher than renal clearance.

The skeletal uptake is a function of the number of bone metastases and the extent of bone turnover.

Remaining unbound bisphosphonate is eliminated by kidney filtration and active tubular secretion.

Associated with osteonecrosis of the jaw with high dose intravenous formulations as part of cancer treatment but also reported to occur with oral agents to treat or prevent osteoporosis.

Histologically the osteonecrosis of the jaw lesion is the same as that of osteoradionecrosis.

Hypothesized that the physiological stresses on the jaw demanding repair of micro-defects are inhibited by hypovascular and hypodynamic effects induced by bisphosphonates causing decreased ability for repair, resulting in osteonecrosis.

Can decrease progression of osteoporosis but also prevents the development the development of atherosclerosis and reduce total mortality rate (Lyles KW).

Data suggests inhibition on endothelial proliferation, adhesion and capillary formation suggesting an antiangiogenic mechanism.

Use is associated with increased incidence of acute myocardial infarction (Pittman CB et al).

May decrease VEGF levels.

General guidelines for the use of bisphosphonates treating individuals with a 10 year major osteoporotic risk of more than 20% or hip fracture risk of more than 3%.

Adverse events with nitrogen containing agents are gastrointestinal intolerance with oral administration, short-lived acute phase reactions with fever, myalgias, flu-like symptoms with intravenous administration.

May be associated with bone, joint and muscle pain.

Observational studies suggest 25% of patients taking oral risendronate and 20.1% of individuals taking alendronate report musculoskeltal adverse effects (Bock O).

In a retrospective study of 65 years or older veterans with a hip or vertebral fracture treated for 1 year or more of bisphosphonate therapy there was no increase in rate of diffuse musculoskeltal pain (Caplan L).

Bisphosphonates less effective in protecting bone mineral density in patients with glucocorticoid induced osteoporosis than in patients with other forms of osteporosis, because glucocorticoids antagonize the effects of nitrogen containing bisphosphonates in inducing apoptosis of osteoclasts and inhibiting bone resorption.

Bisphosphonates in the treatment of glucocorticoid induced osteoporosis is not as good as in the treatment of postmenopausal osteoporosis.

Bisphosphonates in glucocorticoid induced osteoporosis intravenous therapy may be preferable to oral treatment in patients on prolonged glucocorticoid therapy.

Estimated that maximal absorption of alendronate orally is about 0.7% and the lower molar potency of alendronate is lower than that of intravenous zoledronic acid by a factor of 10.

Long-term use may affect calcium metabolism adversely in patients with osteoporosis and Paget’s disease of the bone with hypocalcemia and resultant secondary hyperparathyroidism: Suggesting calcium and vitamin D supplements should be used in patients on long-time therapy (Landman JO).

Women receiving osteoporosis medications should have adequate intake of calcium, 1000-1200 mg daily, and vitamin D 600-800 IU daily.

May cause uveitis, conjunctivitis, episcleritis and scleritis.

Fewer than half of patients prescribed a bisphosphonate are taking the medication after 1 year.

Pamidronate and zoledronic acid stimulate subgroup of T cells activating them to release cytokines that contribute to immunologic autoimmune reactions seen in uveitis and scleritis.

May be associated with orbital inflammatory disease caused by release of cytokines IL-1 and IL-6.

Statistically significant benefit of recurrence risk in early stage breast cancer with the use of bisphosphonates in premenopausal women treated with medical ovarian ablation and tamoxifen or aromatase inhibitors (ABCSG-12 trial).

An analysis of 13 trials involving 6886 patient’s randomized to treatment with bisphosphonates, or either placebo or no treatment in the adjuvant chemotherapy management of breast cancer resulted in: No reduction in the overall number of deaths, bone metastases, overall disease recurrence, distant relapse, visceral recurrence, or local relapse, therefore adjuvant bisphosphonate should not be recommended routinely. (Davide M).

Bisphosphonates used for 1 year in postmenopausal women resulted in fewer breast cancers compared to control group with a hazard ratio of 0.61(Breast Cancer in Northern Israel Study, Rennert G et al).

Women’s Health Initiative study indicated a 31% lower risk of invasive breast cancer among bisphosphonate users.

Bisphosphonates as adjuvant therapy reduces bone recurrence by 34% and breast cancer death by 17%, only in postmenopausal women and those women who have had chemotherapy induced menopause: Indicating bisphosphonates can exert an anticancer effect in breast cancer patients (Coleman R).

Current guidelines call for 3 to 5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.

 

 

Results,however, show no difference in disease-free survival, distant disease-free survival, and overall survival ― regardless of menopausal status ― between the 1540 women who received intravenous zoledronate over a 5- year period and 1447 women who received such therapy over a 2-year period.

 

 

There was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis.

 

 

There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. 

 

 

10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up, vs 7.2% in the 2-year group.

 

 

Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate ― including 7.6% with grade 3/4 events ― vs just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.

 

 

In the 5-year group, 8.3% of partients experienced bone pain and 5.1% experienced arthralgia, vs 3.7% and 3.1%, respectively, in the 2-year arm.

 

 

Fractures were reported in 14 women in the 5-year group but in only three in the 2-year arm.

 

 

Jaw necrosis, was reported in 11 women in the 5-year group and in five in the 2-year group.

The use of bisphosphonates in metastatic breast disease is a palliative measure and has no impact on overall survival.
The use of bisphosphonates in breast cancer should be accompanied by calcium, and vitamin D supplementation.

Osteonecrosis of the jaw and atypical femoral fractures are rare events, but have serious potential harms.

The frequency of osteonecrosis of the jaw in patients receiving high dose IV bisphosphonates for management of hypercalcemia of malignancy is 1-15%, the incidence of osteonecrosis of the jaw in patients with osteoporosis receiving oral or IV bisphosphonates is substantially smaller between one in 10,000 and 1 in 100,000 per year of use.

Atypical fractures have been reported in patients receiving bisphosphonate treatment for 3-8 years with a very low rate of new bone formation suggesting over suppression of bone turnover by bisphosphonates.

Atypical stress fractures in subtrochanteric and femoral shafts occuring in patients receiving bisphosphonates with radiologic features including transverse fracture line originating at the abnormal thickening of the lateral cortex of the femoral shaft.

Atypical femoral fractures from bisphosphonates occur with minimal or no trauma often precededby prodromal thigh pain for a number of weeks.

Atypical femoral fractures-low-trauma subtrochanteric or femoral shaft fractures with an unusual radiologic features including a transverse morphology and thickened cortices, typically occur with little or no antecedent trauma, may be preceded by groin pain, and may occur bilaterally.

Atypical fracture risk more than doubles when bisphosphonates are taken for more than 5 years (Park-Wylie LY et al).

The risk of atypical femur fracture increases with longer duration of bisphosphonateS and rapidly decreases after its discontinuation (Black DM).
In the above study Asians had a higher risk of atypical femur fracture then whites.
In the above study the absolute risk of a typical femur fracture remain very low as compared with reductions in the risk of hip and other fractures with this fascinate treatment.

Atypical femoral fractures require surgical management and may be associated with delayed healing.

Bisphosphonate use is associated with a 1.7 fold increase risk of atypical femoral fractures, the absolute risk of atypical femoral fractures among bisphosphonate users treated for five years or less is very low.

It is estimated that for every 10,000 women treated with bisphosphonates for three years, 130 hip fractures will be prevented at the cost of one atypical femoral fracture.

The incidence of atypical femoral fracture increases with a longer duration of treatment with bisphosphonates.

Age adjusted incident rates rise from 1.8 per 100,000 persons per year with a two year exposure up to 113 per hundred thousand persons per year with an 8-10 year exposure.

Bone turnover markers have shown sustained decreases of 30-50%.

Atypical subtrochanteric hip fractures, unlike the more common hip fractures involving the femoral neck or intertrochanteric region, where typically there is no prodrome, various weeks or months of pain at the site of the fractures in bisphosphonate treated patients.

Atypical subtrochanteric hip fracture patients report pain deep within the thigh, often exacerbated by weight-bearing, and experience hearing and feeling fractures with nontraumatic activities.

Atypical bone fractures have radiologic features of thickening of the femoral cortex, transverse fracture and cortical beak.

Atypical fractures bisphosphonate users are infrequent and should not preclude initiation of therapy in patients at risk for skeletal events.

Between 20-35% of women receiving the agents for metastatic breast cancer do not adequately have osteoclast suppression, as measured by bone turnover markers such as urinary levels of N-telopeptide fragment of collagen ( Lipton A et al).

Not all bisphosphonates reduce the risk of all fractures equally.

All bisphosphonates lower the risk of spine fractures.
Alejandronatr, risendronate, and zoledronate are the most commonly recommended because they also lower the risk of non-spine fractures, including hip fractures.

Alendronate, risendronate and zoledronic acid all reduce the risk for hip, vertebral, and non vertebral/nonhip fractures in their trials.

Ibandronate has not been shown to reduce the risk for hip fractures and has a variable is efficacy and non vertebral/nonhip fracture reduction, but it does reduce the risk for vertebral fractures as all other agents do.

Ibandronate is therefore considered a second agent for osteoporosis.

Trials for alendronate and ibandronate demonstrate reduction in fracture risk at three years, whereas risedronate and zolendronic acid demonstrate a benefit in just one year of therapy.

Optimal duration of bisphosphonate therapy has not been demonstrated as prolonged therapy may increase the risk for atypical fractures as they impair bone remodeling.

Bisphosphonate have a long half life in bone and stopping bisphosphonates does not result in cessation of action.

Randomized controlled trials evaluating the benefits of continuing versus discontinuing bisphosphonate treatment showed that in treatment naive woman who receiverd zolendronate for three years or alendronate for five years, continuation inconsistently reduced vertebral fracture outcomes and did not reduce vertebral fractures: indicating fracture risk reduction may persist years after discontinuation oof bisphosphonate treatment.

3 to 5 years of continued treatment is generally recommended as initial treatment for osteoporosis.

High risk patients may benefit from treatment longer than five years.

Oral bisphosphonates should be taken first thing in the morning with a full 8 ounce glass of plain water and one should remain upright and wait 30-60 minutes before lying down, drinking or eating.
Sitting up or standing helps ensure that the medication is absorbed and reduces side effects.

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