111. Watts NB, Diab DL. Long-term use of - Padis

Bisphosphonates use and oral surgery : prevention and treatment of the

Bisphosphonates-related Osteonecrosis of the Jaw

1. Introduction

1.1

Bisphosphonates

Bisphosphonates (BPs) are medications used in the treatment of a variety of metabolic and oncologic bone diseases.

BPs were originally synthesized in the 19 th century in Germany 1 , and due to their ability to inhibit calcium carbonate precipitation, initially used in the textile, fertilizer and oil industries as antiscaling and anticorrosive agents in washing powders and water and oil brines to prevent the deposition of calcium carbonate scale 2 .

In the 1960’s, in vitro experiments revealed that BPs inhibit calcium phosphate dissolution 3 , and it was this observation that led to the hypothesis that they could be used to prevent bone resorption in vivo 2 .

Then BPs have been gradually improved in the structure so as to create molecules that effectively inhibit bone resorption with a mode of action not mediated by their physiochemical inhibition of crystal dissolution, but rather by their cellular effects on osteoclastic activity 4 .

1.2

Structural characteristics and mechanisms of action

BPs are synthetic compounds with a chemical structure similar to that of inorganic pyrophosphate

(PPi), an endogenous regulator of bone mineralization 5 present as product of several body’s synthetic reactions and usually detected in blood and in urine.

Some studies since the 1960s reported that PPi was able to bind hydroxyapatite crystals and to regulate bone mineralization 6 . Like their endogenous analogue PPi, BPs are characterized by a very high affinity for bone tissue, due to their ability to bind to hydroxyapatite crystals. For this reason BPs are rapidly cleared from the circulation and bind to bone mineral surfaces in vivo at sites of active bone remodeling, particularly in areas undergoing osteoclastic resorption. Nevertheless they suppress bone resorption, by means of a reduction in osteoclast activity 7-9 . The core structure of BPs differs only slightly from PPi, showing a central phosphonate carbon phosphonate (P-C-P) structure, instead of oxygen (P-O-P styructure), that joints two side chains designed R1 and R2. In most currently used BPs the R1 chain

1

is a hydroxyl group attached to carbon. The P-C-P core gives the bisphosphonates their ability to strongly bind hydroxyapatite cristals in bone, while the hydroxyl further increases the BPs ability to bind divalent metal ions such as calcium and magnesium. Therefore, the phosphate and hydroxyl groups work together to create a tertiary, rather than a binary, interaction between the bisphosphonate and the bone matrix, giving this compounds their specific affinity for bone 10 . As the

P-C-P group is highly resistant to enzymatic hydrolysis, BPs are incorporated into the skeleton and stored there until being locally released upon bone remodeling 11 .

Binding affinity and antiresorptive potency differ among the compounds. The R1 chain influences the binding affinity, while the R2 side chain the antiresorptive potency. Modifications of R2 side chain allow for a variety of agents. The presence of a nitrogen into the R2 chain increases the BPs antiresorptive potency by 10 to 10,000 in comparison with first generation non-nitrogen containing

BPs. Chemical structure and antiresorptive potency of existing compounds are available in tables 1 and 2.

Table 1 – Non-aminobisphosphonates: name, molecular formula and relative potency of existing compounds

GENERIC DRUG NAME

CLODRONATE

CLASS

NON-AMINO

BP

CHEMICAL NAME

DISODIUM

(DICHLOROMETHYLENE)

DIPHOSPHONATE TETRAHYDRATE

CHEMICAL STRUCTURE POTENCY*

X10

ADMINISTRATION

ROUTE

-ORAL

-INTRAMUSCULAR

-INTRAVENOUS

ETIDRONATE NON-AMINO

BP

DISODIUM DIHYDROGEN

(1-HYDROXYETHYLIDENE)

DIPHOSPHONATE

X10 -ORAL

TILUDRONATE NON-AMINO

BP

DISODIUM DIHYDROGEN

{[(P-CHLOROPHENYL)THIO]

METHYLENE}DIPHOSPHONATE

HEMIHYDRATE

Relative potency demonstrated in inhibiting bone resorption in rats

12

X10 -ORAL

2

Table 2 - Aminobisphosphonates: molecular formula and relative potency of existing compounds

GENERIC DRUG

NAME

ALENDRONATE

CLASS CHEMICAL NAME

AMINO BP AMINOHYDROXYBUTYLIDENE

DIPHOSPHONIC ACID

CHEMICAL STRUCTURE POTENCY*

X>100<1000

ADMINISTRATION

ROUTE

-ORAL

IBANDRONATE

NERIDRONATE

RISEDRONATE

PAMIDRONATE

AMINO BP [1-HYDROXY-3-

(METHYLPENTYLAMINO) PROPY-

LIDENE]DIPHOSPHONIC ACID

AMINO BP

(6-AMINO-1-

HYDROXYHEXYLIDENE)

DIPHOSPHONIC ACID

AMINO BP

SODIUM TRIHYDROGEN

[1-HYDROXY-2-(3-PYRIDYL)

ETHYLIDENE]DIPHOSPHONATE

AMINO BP

AMINOHYDROXYPROPYLIDENE

BISPHOSPHONATE

ZOLEDRONATE AMINO BP (1-HYDROXY-2-IMIDAZOL-1- YL-

PHOSPHONOETHYL)

BISPHOSPHONIC ACID

MONOHYDRATE

* Relative potency demonstrated in inhibiting bone resorption in rats

12

X>1000<10,000

X100

-ORAL

-INTRAVENOUS

-INTRAMUSCULAR

-INTRAVENOUS

X>1000<10,000

X100

-ORAL

-INTRAVENOUS

X>10,000 -INTRAVENOUS

3

The less potent non-nitrogen containing BPs (etidronate, clodronate, tiludronate) are taken up by osteoclasts from the bone mineral surface and become incorporated into molecules of newly formed adenosine triphosphate (ATP) by the class II aminoacyl–transfer RNA synthetases.

Intracellular accumulation of these nonhydrolyzable ATP analogues interferes with enzymatic activity 13 and induces osteoclast cells death with an overall decrease in the turnover of bone 14 .

Mammalian cells metabolize clodronate to adenosine 5'-[beta],[gamma]-dichloromethylene) triphosphate, leading to depletion of intracellular ATP, inhibition of protein synthesis and accumulation of a toxic ATP analog. This cascade of events induces impaired cellular activity and apoptosis.

The more recent nitrogen-containing bisphosphonates (neridronate, alendronate, risedronate, ibandronate, pamidronate and zoledronic acid), also called amino-bisphosphonates for the presence of a nitrogen atom in the alkyl chain of the molecule, have greater potency, faster efficacy, and more persistent inhibitory effects on bone turnover 15 .

They are internalized by active osteoclasts and inhibit farnesyl pyrophosphate synthase (FPS), an enzyme of the mevalonate pathway of cholesterol synthesis 16 . FPS normally stimulates isoprenylation, a process that activates small GTP-binding proteins (such as Rab, Rac, Ras and Rho) that are responsible for cytoskeletal integrity and intracellular signaling. The consequence is the suppression of osteoclast activity, loss of osteoclast cytoskeletal integrity and ruffled border necessary for local generation of H+ and bone resorption 17-20 , and ultimately apoptosis 21 .

Furthermore Rho and Rac are normally required for the osteoclasts maturation. BPs by inhibiting the geranylgeranylation process will impair proper osteoclast differentiation and survival 22, 23 . Rho and

Rac play also a leading role in regulation of apoptosis. Risedronate, due to inhibited isoprenylation, moves Ras from membrane to cytosol, induces mitochondrial membrane depolarization, cytochrome C release, activation of the caspase cascade and DNA fragmentation 24 . There is also evidence that nitrogen-containing bisphosphonates (N-BPs) decrease osteoclasts recruitment 25 and induce osteoblasts to produce an osteoclast resorption inhibitor 26 . BPs appear to be involved in reducing osteoclastic activity by four main mechanisms of action: 1) inhibition of osteoclastic maturation 2) inhibition of osteoclastic recruitment 3) inhibition of osteoclastic resorption of bone 4) induction of osteoclastic apoptosis.

BPs also affect osteoclast activity indirectly by acting on bone marrow precursor cells and osteoblasts. Usually, osteoblasts play a role in enhancing osteoclast recruitment and activation through the interaction between the osteoblast cell surface-receptor activator of NFjB ligand

(RANKL) and RANK on hematopoietic osteoclast precursor cells.

4

To keep this interaction under control, osteoblasts also secrete osteoprotegerin (OPG), a soluble decoy receptor, that competes with RANKL for RANK; the OPG-RANK binding inhibits osteoclast recruitment and keeps in check the osteoclast to osteoblast balance. In normal bone tissue between osteoblasts and osteoclasts there is a strong functional relationship and an intensive exchange of information aimed at maintaining the balance between bone resorption and formation.

Osteoblasts, after secretion of the osteoid, become osteocytes and let themselves to be trapped into small cavities within the newly formed bone matrix, called osteocyte lacunae and keep themselves lively and interconnected with other ones. From each osteocyte lacuna slender canaliculi radiate and penetrate the adjacent lamellae to anastomose with the canaliculi of neighboring lacunae, thus forming a system of cavities interconnected by minute canals and supplied with advanced mechanoreceptors, that allow them to regulate bone mineralization according to functional needs.

BPs decrease RANKL expression and enhance OPG secretion by osteoblasts and bone marrow stromal cells, so that RANK–RANKL interaction is disrupted; the result is suppression of osteoclast recruitment and reduction in bone resorption 27 .

The main target of BPs are osteoclasts, osteoblasts, bone marrow cells, but some evidence exists that repeated administrations over extended periods can provide a direct anti-neoplastic therapeutic action, possibly related to induction of tumor cells apoptosis by affecting the mevalonate pathway 28 , as well as reducing growth factor release 9, 29 and inhibiting cell adhesion to bone matrix in vivo 30 ; Pamidronate has even been demonstrated to have a direct apoptotic effect on certain myeloma cell lines 31 .

In addition, BPs showed the power to inhibit numerous matrix metalloproteinases (MMPs) (e.g.,

MMP-2, -9, and -12) involved in cancer growth and metastasis 32 , and anti-angiogenic properties decreasing endothelial cell proliferation and capillary formation. Particularly, endothelial cell proliferation, adhesion and migration are inhibited by zoledronic acid in vitro 33 , while both nitrogen and non-nitrogen containing bisphosphonates have been demonstrated to inhibit revascularization of tissue in vivo and angiogenesis 34, 35 .

In alveolar bone, over-accumulation of BPs can cause a lack of capillary formation and a decrease in the blood flow 34 .

All the events mentioned above are involved in cancer growth and metastasis. This is the biologic rationale of the effectiveness of BPs in reducing skeletal complications of cancer.

1.3

Pharmacodynamics of Bisphosphonate Medications

5

This class of medications in general is characterized by poor bioavailability, short plasma half-life and absence of systemic metabolism. When taken orally, BPs must be taken after a prolonged fast

(usually in the early morning), with water only, followed by 30–60 min with nothing else by mouth to allow for adequate absorption. Under ideal conditions, less than 1% of an orally administered dose is absorbed; taking a BP with food or anything containing divalent cations will completely block its absorption .

The majority of BPs displays a biphasic elimination pattern. About 50% of the absorbed drug is selectively retained in the skeleton, while the remaining 50% is excreted via the kidneys in the first

24-72 hours. Renal clearance of BPs correlates significantly with creatinine clearance, so that most

BPs are contraindicated in patients with severe renal insufficiency. Skeletal uptake and retention are primarily dependent on host factors (renal function, prevalent rate of bone turnover, and binding site availability) and BPs affinity for bone matrix 36 . The BPs retained in the bone matrix are presumed to be sequestered there for an extended time, until they are released slowly back into the systemic circulation by normal bone turnover 37 . BPs are excreted unchanged from the body because they are not modified by systemic metabolism. The terminal bone elimination half-life of this medications varies according to the compound and can be extremely long (e.g., ibandronate,

10–60 h; zoledronic acid, 146 h; risedronate, 480 h; pamidronate, 300 days; and alendronate, more than 10 years) 38 .

Furthermore, data regarding BPs elimination from bone, derived from animal or human studies, estimate that the terminal half-life of BPs might not necessarily depend only on the specific drug, but also on the physiological rate of bone turnover of the subject.

At a given trabecular bone surface, the human bone matrix undergoes complete remodeling once every 2 years, while rats appear to replace their skeletal segments more rapidly, once every 1 month.

These differences can explain the reported terminal bone half-life of alendronate, which appeared to be variable from

200 days in rats, 3 years in dogs, up to 12 years in humans. So, once incorporated into bone tissue,

BPs can persist for up to 10 years, depending on skeletal turnover time 39 .

As the skeletal capacity is large, the bone-binding sites are unlikely to be saturated, so being virtually endless. BPs drugs differ in the strength of binding to bone. The rank order for binding affinity is zoledronate greater than alendronate greater than ibandronate greater than risedronate.

Higher-affinity BPs will bind avidly to the bone surface but will spread through bone more slowly and have less access to the osteocytes network. Lower affinity agents will be distributed more widely through the bone tissue and also have a shorter residence time if treatment is stopped 40 . The profile of binding affinity and antiresorptive potency specific of each BP could explain the existence of clinically meaningful differences in the speed of onset and offset of effect, the degree of reduction of

6

bone turnover, uptake in cortical versus trabecular bone and types of antifracture effect, such as vertebral versus nonvertebral. In general the reduction of bone turnover appears to be dose and compound dependent, with a maximum effect in 3–6 months that, with continued treatment, is maintained in a new steady state for 10 yr 41,42 and perhaps longer.

1.4

Medical use of Bisphosphonates

BPs are recommended to control medical conditions associated with an excessive or imbalanced skeletal remodeling, in which osteoclast and osteoblast activities are not harmonized/synchronized, leading to undue osteoclast-mediated bone resorption. BPs, according to their ability to modulate osteoclast activity, have become the primary therapy for managing cancer-induced bone diseases such as osteolytic tumor localizations and hypercalcemia of malignancy. Furthermore a substantial clinical benefit has been reported in the treatment of several metabolic bone diseases associated with excessive bone resorption, such as osteopenia, multiple forms of osteoporosis (juvenile, postmenopausal, glucocorticoid-induced, transplant-induced, immobility-induced, androgen-deprivationrelated), destructive arthropathy, Paget’s disease. They have also found off-label use in a number of bone-affecting diseases such as osteogenesis imperfecta 43 , fibrous dysplasia 44 , and Gaucher’s disease 45 .

The range of bisphosphonates currently available in Italy, as well as their indications and dosage are outlined in Table 3.

7

Table 3 - BPs approved in Italy with their officially authorized clinic use

ACTIVE SUBSTANCE

ETIDRON

TRADE NAME AVAILABLE FORMS

300 MG TABLETS" ETIDRONATE DISODIUM

CLODRONATE DISODIUM ACIDO CLODRONICO EG

CLASTEON

CLIMACLOD

CLODEOSTEN

CLODRONATO ABC

CLODRONATO ABC

CLODRONATO TEVA

CLODY

DIFOSFONAL

100 MG/3,3 ML INJECTABLE

300 MG INJECTABLE SOLUTION

100 MG/3,3 ML INJECTABLE SOLUTION



300 MG/10 ML IV INFUSION




MARKETING AUTHORISATION HOLDER

ABIOGEN PHARMA SpA

THERAPEUTIC AREA

PAGET ‘S DISEASE

EG SpA

ABIOGEN PHARMA SpA

MASTELLI Srl

CRINOS SpA

ABC FARMACEUTICI SpA

ABC FARMACEUTICI SpA

TEVA ITALIA Srl

PROMEDICA Srl

SPA (SOC.PRO.ANTIBIOTICI)SpA

OSTEOLYTIC METASTASES

MULTIPLE MYELOMA

PRIMARY HYPERPARATHYROIDISM

PREVENTION AND TREATMENT OF

POSTMENOPAUSAL OSTEOPOROSIS

-

CLODRONATE DISODIUM

TETRAHYDRATE

DIFOSFONAL

DIFOSFONAL

DISODIO CLODRONATO ALTER

MOTICLOD

OSTEONORM

OSTEOSTAB

ACIDO CLODRONICO MYLAN

GENERICS

ACIDO CLODRONICO

ACIDO CLODRONICO

CLASTEON

CLODRON


400 MG CAPSULES






100 MG/3.3 ML INJECTABLE SOLUTION


400 MG CAPSULE S

400 MG CAPSULE S



LABORATORI ALTER Srl

LISAPHARMA SpA

FARMAC.CABER SpA

ROTTAPHARM SpA

MYLAN SpA

SANDOZ SpA

SANDOZ SpA

ABIOGEN PHARMA SpA

FIDIA FARMACEUTICI SpA

TRAXOVICAL 100 MG/3,3 ML INJECTABLE SOLUTION ATHENA PHARMA ITALIA Srl

8

CLODRONATE DISODIUM

LIDOCAINE CHLORHYDRATE

ALENDRONATE DISODIUM

ALENDRONATE SODIUM

CLODRON

100 MG + 33 MG/3,3 ML INJECTABLE

SOLUTION

CLASTEON

CLODY

DIFOSFONAL

NIKLOD

ACIDO ALENDRONICO FG

ACIDO ALENDRONICO FIDIA

ACIDO ALENDRONICO GERMED

ACIDO ALENDRONICO SIGMA TAU

GENERICS

ADRONAT





70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

ADRONAT

ALENDRONATO AHCL

ALENDRONATO ALMUS

ALENDRONATO ALTER

ALENDRONATO ARROW

10 MG TABLETS

70" 4 TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

ALENDRONATO DOC GENERICI

ALENDRONATO EG

70 MG TABLETS

70 MG TABLETS

ALENDRONATO MYLAN GENERICS 70 MG TABLETS

ALENDRONATO PENSA 70 MG TABLETS

ALENDRONATO RANBAXY ITALIA 70 MG TABLETS

ALENDRONATO RATIOPHARM

ALENDRONATO SANDOZ

ALENDRONATO TEVA

ALENDROS

ALENDROS

ALENIC

ASTON

DORYX

DRALENOS

DRONAL

GENALEN

GENALEN

GLAMOR

LOSS

NOFRATTIL

PORODRON

REALEN

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70" 4 TABLETS

10MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

10 MG TABLETS

70" 4 TABLETS

10 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

70 MG TABLETS

ADROVANCE

ADROVANCE

FOSAVANCE

FOSAVANCE

70MG/70 TABLETS

70MG/5600 UI TABLETS

70MG/5600 UI TABLETS

70 MG/70 MCG TABLETS


ABIOGEN PHARMA SpA

PROMEDICA Srl


I.B.N. SAVIO Srl

FG Srl


GERMED PHARMA SpA

SIGMATAU GENERICS SpA

NEOPHARMED Srl

NEOPHARMED Srl

ACCORD HEALTHCARE ITALIA Srl

ALMUS Srl

LABORATORI ALTER Srl

ARROW GENERICS LTD

DOC GENERICI Srl

EG SpA

MYLAN SpA

PENSA PHARMA SpA

RANBAXY ITALIA SpA

RATIOPHARM ITALIA Srl

SANDOZ SpA

TEVA ITALIA Srl

ABIOGEN PHARMA SpA

ABIOGEN PHARMA SpA

EPIFARMA Srl

BIOHEALTH PHARMACEUTICALS Srl

CRINOS SpA

SEGIX ITALIA Srl

SIGMATAU IND.FARM.RIUNITE SpA

IST.GENTILI SpA

IST.GENTILI SpA

AGIPS FARMACEUTICI Srl

SO.SE.PHARM Srl

S.F.GROUP Srl

PHARMEG Srl

IST.CHIM.INTERNAZ. RENDE Srl

ADDENDA PHARMA Srl

ADDENDA PHARMA Srl

MERCK SHARP & DOHME SpA

MERCK SHARP & DOHME SpA

POSTMENOPAUSAL OSTEOPOROSIS

POSTMENOPAUSAL OSTEOPOROSIS IN PATIENTS

WITH VITAMIN D DEFICIENCY

9

IBANDRONATE SODIUM

MONOHYDRATE

NERIDRONATE SODIUM

VANTAVO

VANTAVO

BONDRONAT

BONDRONAT

BONVIVA

BONVIVA

NERIXIA

NERIXIA

RISEDRONATE SODIUM ACTONEL

PAMIDRONATE SODIUM

PAMIDRONATE DISODIUM

ACTONEL

ACTONEL

ACTONEL

AVESTRA

OPTINATE

OPTINATE

OPTINATE

RISEDRONATO EG

RISEDRONATO GERMED

RISEDRONATO GERMED

RISEDRONATO MYLAN

RISEDRONATO RANBAXY

RISEDRONATO SANDOZ

RISEDRONATO TEVA

AMIDROX

AMIDROX

AMIDROX

AMIDROX

AMIDROX

AREDIA

AREDIA

AREDIA

AREDIA

70 MG/5600 UI- TABLETS

70 MG/2800 UI- TABLETS

50 MG TABLETS


150 MG TABLETS

IV INFUSION PREFILLED SYRINGE

100 MG IV INFUSION


30 MG TABLETS

5 MG TABLETS

35 MG TABLETS

75 MG TABLETS

75 MG TABLETS

35 MG TABLETS

5 MG TABLETS

75 MG TABLETS

35 MG TABLETS

5 MG TABLETS

35 MG TABLETS

35 MG TABLETS

35 MG TABLETS

35 MG TABLETS

35 MG TABLETS

3MG/ML IV INFUSION

3MG/ML IV INFUSION

3MG/ML IV INFUSION

3MG/ML IV INFUSION

3MG/ML IV INFUSION





NEOPHARMED SpA

NEOPHARMED SpA

ROCHE SpA

ROCHE SpA

ROCHE SpA

ROCHE SpA

ABIOGEN PHARMA SpA

ABIOGEN PHARMA SpA

WARNER CHILCOTT ITALY Srl




SANOFI-AVENTIS SpA

GRUPPO LEPETIT Srl

GRUPPO LEPETIT Srl

GRUPPO LEPETIT Srl

EG SpA

GERMED PHARMA SpA

GERMED PHARMA SpA

MYLAN SpA

RANBAXY ITALIA SpA

SANDOZ SpA

TEVA ITALIA Srl

CRINOS SpA

CRINOS SpA

CRINOS SpA

CRINOS SpA

CRINOS SpA

NOVARTIS FARMA SpA

NOVARTIS FARMA SpA

NOVARTIS FARMA SpA

NOVARTIS FARMA SpA

PREVENTION OF SREs (INTRACTABLE BONE PAIN,

PATHOLOGICAL FRACTURES, NEED FOR BONE SURGERY

OR PALLIATIVE RADIOTHERAPY, HYPERCALCEMIA,

NERVE ROOT AND SPINAL CORD COMPRESSION) IN

PATIENTS WITH BREAST CANCER AND BONE

METASTASES

POSTMENOPAUSAL OSTEOPOROSIS WITH INCREASED

RISK FOR VERTEBRAL FRACTURES

OSTEOGENESIS IMPERFECTA

PAGET’S DISEASE

TREATMENT OF POSTMENOPAUSAL

OSTEOPOROSIS WITH INCREASED RISK FOR

VERTEBRAL AND HIP FRACTURES

PREVENTION OF POSTMENOPAUSAL AND

GLUCOCORTICOID-INDUCED

OSTEOPOROSIS

HYPERCALCEMIA OF MALIGNANCY

OSTEOLYSIS FROM METASTATIC BREAST

CANCER

ADVANCED MULTIPLE MYELOMA

10

ZOLEDRONIC ACID

MONOHYDRATE

PAMIDRONATO DISODICO HIKMA 30 MG/ 10 ML IV INFUSION




PAMIDRONATO DISODICO

HOSPIRA


HOSPIRA

15/MG/5 ML IV INFUSION



HOSPIRA


HOSPIRA

PAMIDRONATO RATIOPHARM




PAMIDRONATO TEVA




TEXPAMI

TEXPAMI

TEXPAMI

TEXPAMI

30/MG/10 ML IV INFUSION


3 MG/ML (10 ML) IV INFUSION




3MG/ML (20 ML) IV INFUSION

3MG/ML (30 ML ) IV INFUSION



90 MG/ 10 ML IV INFUSION




ACLASTA 100 ML /5 MG IV INFUSION

HIKMA ITALIA SpA

HIKMA ITALIA SpA

HIKMA ITALIA SpA

HIKMA ITALIA SpA

HOSPIRA ITALIA Srl

HOSPIRA ITALIA Srl

HOSPIRA ITALIA Srl

HOSPIRA ITALIA Srl





TEVA ITALIA Srl

TEVA ITALIA Srl

TEVA ITALIA Srl

TEVA ITALIA Srl

PHARMATEX ITALIA Srl




NOVARTIS FARMA SpA

ZOMETA 4 MG/5 ML IV INFUSION NOVARTIS FARMA SpA

PAGET’S DISEASE

PREVENTION OF SRES (INTRACTABLE BONE

PAIN, PATHOLOGICAL FRACTURES, NEED FOR

BONE SURGERY OR PALLIATIVE

RADIOTHERAPY, HYPERCALCEMIA, NERVE

ROOT AND SPINAL CORD COMPRESSION) IN

PATIENTS WITH PRIMARY OR SECONDARY

BONE MALIGNANCIES

HYPERCALCEMIA FROM NEOPLASTIC BONE

LESIONS

11

1.4.1

Bone malignancy

Many cancers are osteotropic and either grow primarily in the bone marrow, such us multiple myeloma 46,47 , or metastasize to the skeleton from an elsewhere primary malignancy. Skeleton is the most common metastatic site, and 90% or more of oncologic patients with advanced disease develop bony secondary lesions 48 .

Bone metastases most frequently result from advanced metastatic breast or prostate cancers 49 , but less frequently they can occur in patients with lung, renal and thyroid carcinomas 50 . Typically metastases from breast cancer or multiple myeloma show an osteolytic aspect, whereas those from prostate cancer are predominantly osteoblastic, although both processes in many patients may coexist 47,51 . However, in both osteolytic or osteoblastic clinical feature, the normal bone homeostasis is altered by uncontrolled osteoclastic remodeling and by abnormal osteoblastic bone formation, resulting in reduced bone strenght and susceptibility to fractures.

The most affected anatomical areas are vertebrae, pelvis, ribs, femur and skull 52 , all located in the axial skeleton, reflecting the distribution of the red marrow. Metastatic bone disease is a major cause of morbidity and mortality for oncologic patients. Patients with bone malignancies are exposed to possible skeletal-related events (SREs) such as intractable pain requiring opioid analgesics, pathological fracture and subsequent need for bone surgery or palliative radiation therapy, hypercalcemia of malignancy, infiltration of bone marrow, nerve root and spinal cord compression 53,54 . Each of these conditions complicates their clinical course, negatively affects patients' mobility and functional independence, quality of life, and survival. For these patients is very important that the expansion of skeletal lesions from cancer is limited or stopped. Several clinical trials have been designed to clarify the BPs role in preventing SREs in a variety of bone malignancies.

Multiple mieloma – Multiple myeloma (MM) is a neoplastic disease caused by the monoclonal expansion of malignant plasma cells in the bone marrow, often resulting in devastating bone involvement. Both the first generation non-nitrogen-containing clodronate 55,56 and the more potent second and third generation aminobisphosphonates such as pamidronate 57,58 , ibandronate 59 , and zoledronic acid 60,61 have been studied in multiple myeloma. Berenson reported that pamidronate 90 mg administered as a four-hour intravenous (IV) infusion given every four weeks for nine cycles 57 and

21 cycles 58 significantly reduced the proportion of patients who had any skeletal events during BPs therapy in comparison with placebo group. Although survival was not different between the pamidronate-treated group and placebo group, patients who received pamidronate had significant

12

decrease in bone pain and no deterioration in performance status and quality of life during the period of observation.

Zoledronic acid in two randomized, double-blind, multicenter, comparative trials 60,61 showed to reduce the overall proportion of patients with a SRE and in general the skeletal morbidity rate, similar to pamidronate during a 13 months (2001) and 25 months (2003) follow-up. Also oral clodronate 1600 mg daily appears to be able in reducing the incidence of vertebral and nonvertebral fractures 55 , hypercalcemia, back pain, poor performance status and in prolonging survival time in patients with no skeletal fractures at study entry 56 , when compared with placebo-treated multiple myeloma patients, during a minimum follow-up of two years. At the current state of knowledge intravenously administered BPs have received the role of standard of care to prevent and treat myeloma-associated metabolic bone impairment 62,63 .

Breast Cancer- For patients with bone metastases from breast cancer, treatments with intravenous pamidronate 64-67 , zoledronic acid 68-70 , or ibandronate 71 have been effective in substantially reducing skeletal complications.

When zoledronic acid and pamidronate were directly compared 61,72 , an equivalent ability in reducing the incidence of SREs other than hypercalcemia was reported, but zoledronic acid in comparison with pamidronate significantly reduced proportion of patients requiring radiation therapy and, in the subgroup of patients receiving hormonal therapy, significantly increased the median time to first SRE.

Also high-dose oral clodronate 73,74 and ibandronate 75,76 , have shown some benefit in the palliative treatment of these patients reducing cumulative incidence of SREs and need for radiation therapy and surgery to bone.

In addition to providing skeletal-related event (SRE) benefits, zoledronic acid has been shown to have a direct anticancer ability in reducing both the size of the invasive tumor mass and the amount of circulating and disseminated cancer cells, with a protective effect on disease recurrence 77 .

A possible preventive role of BPs towards the development of bone metastases from breast cancer is supported by the finding that women affected by localized non-metastatic mammary cancer treated with clodronate for two years showed during BPs exposure statistically significant decrease in metastases development, and a long-term reduction of overall mortality 78 . Current standards of care for the prevention and treatment of SREs in patients with breast cancer with bone metastases include intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks 79 .

13

Prostate Cancer - Skeletal metastases from prostate cancer have most commonly osteoblastic clinical features, but however bone involvement results in a disrupted bone metabolism and increased biochemical markers of bone resorption 80 . Only zoledronic acid appeared to reduce SREs in patients with prostate cancer and metastatic bone disease 81-83 . Patients with hormone-refractory prostate cancer, treated with 4 mg/8 mg IV zoledronic acid every e weeks for 15 months 81 and 24 months 82 had significantly reduced occurrence of SREs and prolonged time to first SRE in comparison with placebo, while pamidronate with a similar schedule of administration (90 mg IV every 3 weeks for 27 weeks) was not able to reduce neither bone pain nor SRE rate. Oral clodronate versus placebo has been shown to extend the bone progression-free survival (i.e. the time to development of symptomatic or full-blown metastatic disease) and the overall survival time, although this clinical end points did not reach statistical significance 84 . As patients with androgen-sensitive prostate cancer receiving androgen-deprivation therapy can run into impaired skeletal integrity, BPs have been studied as possible solution for this concern. IV pamidronate and zoledronic acid therapy prevented reduced bone mineral density (BMD) at both the hip and the spine in men with nonmetastatic prostate cancer who received hormone therapy 85,86 , and oral risedronate showed to prevent early bone loss and increased bone turnover in these patients 87,88 .

Other Malignancies—Use of BPs in other malignancies less frequently affecting skeletal integrity, such as renal cell carcinoma, lung cancer, colorectal cancer and other solid tumors, has been studied.

Although at the current state of knowledge a limited evidence supports routine use of BPs therapy for malignancies different than multiple myeloma, or breast and prostate cancer metastatic to bone, both

IV zoledronic acid 89,68,90 and IV ibandronate 91 showed to reduce proportion of SREs and delay the onset and progression of skeletal involvement in metastatic lung cancer, renal cancer and various solid tumors, and in bone metastases from colorectal cancer, respectively.

BPs reducing both skeletal-related events (SREs) and hypercalcaemia (HCA) of malignancy, improve quality of life and pain control, and have positive consequences for health services and patients. A decrease in need for orthopaedic surgery, radiotherapy, analgesic use, hospital admissions, time spent in hospital, outpatient visits and community support has been reported on the basis of the best available evidence 48 . An other recently introduced bone modifying agent (subcutaneous denosumab) is also currently being evaluated in the treatment of bone metastases in patients with advanced cancer and multiple myeloma; this human monoclonal anti-RANKL antibody appears to represent a potential novel treatment option with the convenience of subcutaneous administration and minor risk for renal

14

adverse events 92 . However, the current standard of care still recommends use of IV bisphosphonates as very useful and effective therapeutic tools in preventing and treating skeletal-related events (SREs), and in improving global quality of life of patients with advanced cancer and skeletal involvement from metastatic bone disease.

1.4.2

Osteoporosis

The most frequent clinical indication for BPs use is the treatment of osteoporosis (OP). This class of drugs is effective in increasing bone mineral density (BMD) and decreasing bone loss in postmenopausal osteoporosis 93-95 but also in some particular conditions affecting skeletal integrity such as corticosteroid-induced 96,97 and immobility-induced 98,99 bone loss.

OP is the most common systemic skeletal disease encountered in postmenopausal women and almost one third of patients over age 60 are affected. It is characterized by low bone mass, deterioration of bone tissue and disruption of bone architecture, compromised bone strength and increased risk of fracture, particularly vertebral and hip. Osteoporosis is a silent disease until it is complicated by fractures that can occur following minimal trauma, and raise the patient’s rate of associated morbidity, loss of independence, and mortality. OP is a major public health problem whose incidence has been increasing exponentially in contemporary society due to population ageing and prolonged life expectancy. The latter has been increased due to diet, lifestyle and access to medical care, and women typically outliving men by around five years. OP can be prevented and can be diagnosed and treated before any fracture occurs.

Dual-energy x-ray absorptiometry (DXA) measurement of the hip and spine is the technology now used to establish or confirm a diagnosis of osteoporosis, predict future fracture risk and monitor patients by performing serial assessments 100 . BMD evaluation is recommended:

in women age 65 and older and men age 70 and older

in postmenopausal women and men age 50-69 when you have concern based on their risk factor profile or when the patient have had a fracture, to determine degree of disease severity.

Areal BMD is expressed in absolute terms of grams of mineral per square centimeter scanned (g/cm2) and as a relationship to two norms: compared to the expected BMD for the patient’s age and sex (Zscore), or compared to “young normal” adults of the same sex (T-score). The difference between the patient’s score and the norm is expressed in standard deviations (SD) above or below the mean.

Usually, 1 SD equals 10 to 15 percent of the BMD value in g/cm2. Depending upon the skeletal site, a

15

decline in BMD expressed in absolute terms (g/cm2) or in standard deviations (T-scores or Z-scores) begins during young adulthood, accelerates in women at menopause and continues to progress in postmenopausal women and men age 50 and older. The BMD diagnosis of normal, low bone mass, osteoporosis and severe or established osteoporosis is based on the World Health Organization (WHO) diagnostic classification, and osteoporosis is defined by BMD at the hip or spine that is less than or equal to 2.5 standard deviations below the young normal mean reference population (Fig 1).

Fig 1 – Bone mineral density , T-score and Z-score

Spine: L1-L4 BMD gm/cm 2

1.320

1.200

1-080

0.960

0.840

0.720

T

{

Z

{

*

T = -2.0 Z = -0.5

Score

+ 1.0

0.0

- 1.0

- 2.0

- 3.0

- 4.0

20 40 60 80 100

Age

The FRAX ® algorithms ® (www.NOF.org and www.shef.ac.uk/FRAX) give the 10-year probability of fracture. The output is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture).

Economic modeling are performed to identify the 10-year hip fracture risks above which it is costeffective, from the societal perspective, to treat with pharmacologic agents; repeated BMD assessments are necessary every two years or more frequently as measure for monitoring effectiveness of treatment and necessity of further medication intake.

In the last 2 decades, BPs have become the standard of care for postmenopausal osteoporosis because of their ability to resolve the relative imbalance between osteoclastic bone resorption and osteoblastic bone formation, selectively suppressing osteoclast activity and stabilizing bone mineral density.

16

It has been conclusively shown that oral alendronate and risedronate are able to reduce the occurrence of vertebral 101-103 and hip fractures 101,104 , the advancement of spinal deformity and of height loss in women with postmenopausal osteoporosis 105 .

Ibandronate, intravenously or orally administered, seemed to have the power to decrease only the risk of vertebral fracture 106,107 although a larger sample size would have been required to achieve an effect on nonvertebral and hip fractures.

Table 4 shows the relative risk reduction reported for vertebral, nonvertebral and hip fractures in women affected by postmenopausal osteoporosis and treated with the BPs cited above.

Table 4 - Relative risk reduction for vertebral, hip and nonvertebral fractures in women with postmenopausal osteoporosis after a three-year treatment with oral Bisphosphonates.

Fracture site

BPs medication

Alendronate 101 Risedronate

103,104

47 41

Ibandronate

62

107

Vertebral

Hip 51 40 NS*

Nonvertebral 20 39 NS*

* not statistically significant

Although most clinical trials dealing with BPs and reduced bone mass focused on postmenopausal women, apparently similar responses could be expected for men with established osteopenia or osteoporosis 108,109 .

In more recent studies weekly (alendronate, risedronate) or monthly (ibandronate, and risedronate) administrations have been studied as possible treatment schedule and have been demonstrated to be effective in reducing both biochemical markers of bone resorption and changes in BMD measured by

DXA.

Finally, both ibandronate and zoledronic acid as intravenous formulation have been approved for the treatment of postmenopausal osteoporosis, with a quarterly or yearly administration, respectively.

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study, zoledronic acid intravenously administered once a year provided significant reduction in vertebral

(70% less), hip (41% less), and nonvertebral (25% less) fractures, with increased (statistically significant) BMD at the lumbar spine, hip, and femoral neck 110 .

17

Nowadays these administrations, as suitable alternatives of treatment regimen, are often preferred by clinicians because of their power to overcome issues of oral therapy such as gastrointestinal intolerance or poor adherence to therapy schedule.

Multi-specialty councils of medical experts in the field of bone health developed Guidelines as reference points for clinical decision making, on the prevention and treatment of osteoporosis. These basic references are based largely on updated information on the incidence and costs of osteoporosis in order to indicate the level of risk at wich is cost-effective to consider treatment. On the basis of these basic guidelines, each clinician (who often is an endocrinologist, a gynaecologist, a rheumatologist, an orthopaedic, a geriatrician, an health care professional in the field of physical medicine and rehabilitation or of osteopathy), should tailor his recommendations and, in consultation with patient, devise individualized plan for osteoporosis prevention and treatment.

A recently proposed treatment schedule 111 establishes some criteria for clinical decision making :

-in case of a low risk of fracture is reported with BMD, the BPs treatment is not needed, and if the patient is taking a BPs drug yet, it should be discontinued and not restarted until the patient meets treatment guidelines;

-if a mild risk of fractures is present, patient needs treating with BPs for 3–5 years and then a drug holiday is recommended until there is significant loss of BMD or the patient has a fracture; a moderate risk of fracture normally requests a period of 5–10 years of BPs intake, then a drug holiday of 3–5 years or until there is significant loss of BMD or the patient has a fracture;

-a high risk of fracture needs to be treated with BPs for 10 yr, and a drug holiday can be offered of 1–2 years until there is significant loss of BMD or the patient has a fracture.

1.4.3

Other metabolic bone diseases

BPs have shown some usefulness in the treatment of certain metabolic bone diseases other than osteoporosis. In particular, the use of these drugs is fairly consolidated in the treatment of Paget's disease and a good evidence exists for the treatment of osteogenesis imperfecta in children.

Also in other conditions such as Fibrous Dysplasia and Gaucher’s disease, even in absence of strong evidence-based recommendations for their use, BPs have shown encouraging results.

All the metabolic bone diseases cited above, although via different pathogenic mechanisms, are characterized by a progressive involvement of the skeleton with subsequent severe decrease in bone mass and skeletal fragility, worsening bone pain, risk of pathological fractures, spinal and long bones deformities with strong impact on mobility and daily activities of the patient.

18

Paget's disease of bone (PDB) is a common disorder involving one or several skeletal segments characterized by an osteoclast-mediated excessive bone resorption and an osteoblast-mediated accelerated new bone deposition, resulting in abnormal new tissue, immature, weakened, less structurally organized, with collagen fibres randomly arranged instead of physiological parallel orientation 112 . PDB can be asymptomatic but commonly is associated with bone pain, pathological fractures, and nerve compression syndromes. Other complications, as bone deformities including bowing of weight-bearing long bones and skull enlargement, secondary osteoarthritis, hypercalcaemia, hearing loss and sarcomatous degeneration, can dramatically impair the quality of life of sufferers.

BPs, as effective and safe inhibitors of osteoclastic bone resorption, have become over years the therapeutic option of first choice in PDB patients.

A conclusive evidence regarding the ability of BPs to prevent the complications of PDB is lacking 113 .

Nevertheless both oral (such as tiludronate 114 , risedronate 115 , alendronate 116 and intravenously administered (pamidronate 117 , neridronate 118 , and zoledronic acid 119 ) BPs have shown to be effective in achieving clinical, biochemical and scintigraphic remission of the disease, this latter providing greater antiresorptive efficacy and longer-lasting effect.

Osteogenesis imperfecta (OI) includes a set of genetic disorders affecting connective tissue and type I collagen, resulting over time in osteopenia, bone fragility, increased susceptibility to fractures, bone deformities, chronic pain and progressive loss of mobility. IV pamidronate was the drug most studied 120-124 but also oral alendronate 30 and risedronate 125 , as well as IV zoledronic acid 126 , and neridronic acid showed some clinical benefit in terms of reduced incidence of fracture, prevention of bone deformities and increased BMD as measured by dual x-ray absortiometry.

Gaucher’s disease (GD) Gaucher disease is an autosomal recessive inherited defect affecting the lisosomal activity of the enzyme glucocerebrosidase, with consequent lipid storage in the liver, spleen, and bone marrow. The primary treatment of this condition is the enzyme replacement therapy, but generalized osteopenia and focal bone lesions due to skeletal involvement require specific treatment.

IV pamidronate 127-129 was shown to have some usefulness in leading to a normalization of bone density and metabolism, finding an indication in the treatment of patients with severely impaired bone integrity due to GD.

Fibrous dysplasia (FD) is a skeletal disorder due to a disfunction in the mechanism of osteoblastic lineage differentiation and maturation. It is a nonhereditary disease of unknown cause. Monostotic and polyostotic forms exist. FD can be one of the hallmarks that identify McCune-Albright syndrome, where endocrine and skin disorders associate with the most severe form of polystotic bone

19

involvement. The FD patients show bone lesions with tumor-like growth. A replacement of the medullary bone with fibrous tissue takes place, causing expansion and weakening of the affected skeletal segment. In most cases patients are suffering from bone pain, pathological fractures, reduced mobility, severe limitations in daily activities. Especially skull and facial bones involvement are difficult to manage because of nerve compression, loss of vision or hearing, impairement of respiratory function, dysmorphic feature or untractable headache that frequently characterize these localization.

Several observational uncontrolled reports outlined the positive results of BPs drugs in the treatment of children affected by fibrous dysplasia. Particularly, 180mg IV pamidronate (60 mg/day during 3 days) administered every 4 months to 1year, according to alkaline phosphatase level, reduced the incidence of pathological fractures and bone pain, improved radiological features and BMD of the affected sites 130,131 , provided a reduction of markers of bone turnover 132,133 , also in children and adolescents with McCune-Albright syndrome 134,135 .

Some anecdotal reports proposed the possible use of BPs as primary or additional therapy of giant cell lesions of the jaws and osteolysis surrounding falling orthopedic implants 43 .

At the current state of knowledge for all the metabolic bone diseases other than osteoporosis cited above, some questions regarding patients selection, the effectiveness in preventing bone fractures and other long-term complications, the best medication to use, the dosing regimen and duration of treatment still remain unanswered. Focused literature mainly consists of observational open studies, without control. Long-term controlled randomized studied are needed in order to provide strong evidence-based clinical recommendations. Nevertheless some evidence exists that in the treatment of umbalanced osteoclast-mediated bone resorption BPs can play a key role in preventing and treating generalized skeletal involvement as well as focal bone lesions, irrespective of the underlying pathogenetic mechanism of the single specific condition.

1.5

Side effects of Bisphosphonates

Several side effects and adverse events have been related to the intake of BPs drugs. An increased incidence of atrial fibrillation (AF) was reported, following yearly administration of IV zoledronic acid, severe enough to cause disability or hospitalization or even life-threatening events 110 . Wheter this electrophysiologic disorder was related to BPs infusion or this was a chance finding remains an unsolved question, as AF augmented rate was not reported neither in the HORIZON Recurrent Fracture

Trial, in which the AF concern was carefully evaluated 136 , nor in trials dealing with oncologic diseases,

20

where doses 10 times higher were used. Furthermore, recent post-hoc analysis of data from the pivotal Fracture Intervention Trial 137 and from a large population-based case-control study 138 identified a possible correlation between oral intake of alendronate and a slightly increased incidence of AF, while a larger population-based case control study doesn’t support this hypothesis 139 .

A proportion of patients between 10 and 30% following IV nitrogen-containing BPs experiences an

acute phase reaction with transient fever, muscle and joint pain, headache. This flu-like symptoms are probably due to the release of proinflammatory cytokines by peripheral T lymphocytes 140 and usually decrease as early as the second infusion, and only 2.8% of patients still show them after the third dose 110 .

A severe, disabling musculoskeletal pain was reported 141 as an uncommon adverse event distinct from the acute phase reaction, which can occur at any time after starting BPs therapy 142 . The pathogenetic mechanism and the incidence rate of this condition as well as the causal relationship between it and

BPs use therapy are not yet fully established.

Orally administered BPs can induce erosive esophagitis 143,144 , especially in patients already diagnosed with gastroesophageal reflux disease, while the hypothesis of an increased risk of esophageal cancer among patients treated with these medications is not currently supported by scientific evidence 145,146 .

Esophageal irritation and erosion can be minimized by the maintenance of upright posture for 30-60 minutes after taking the medicine, and by the use of weekly rather than daily dosing. Some intravenous preparations are now approved with a yearly schedule of administration for the treatment of osteoporosis and are not associated with irritation of gastrointestinal tract.

Some authors suggest to modulate dose and infusion rate of intravenous BPs in patients with severe renal insufficiency (creatinine clearance < 30 mL / min); in these subjects a concrete possibility of acute

renal failure following IV administration should be considered 147,148 , primarily related to the peak blood concentration. Instead the efficacy and safety demonstrated in patients with moderately reduced renal function justify the use of both oral 149,150 and intravenous 151,152 preparations . In the latter case the risk of renal adverse events seems to be further reduced by maintaining adequate hydration and prolonging the infusion time.

Hypocalcemia was reported following BPs intravenous infusion in patients with high rate of osteoclastmediated resorption, such as in patients with Paget's disease or severe metastatic osteolysis, hypoparathyroidism, renal impairment, deficiency of vitamin D. The intake of Calcium and vitamin D as a dietary supplement appeared to be supportive in preventing this condition.

21

Surprisingly, despite the BPs are the treatment of choice in preventing pathologic fractures due to osteoporosis, has been suggested a possible correlation between prolonged use of these drugs and the occurrence of atypical insufficiency fractures. The hypothesized mechanism is an oversuppression of bone turnover that, extended in time, impairs physiological bone renewal and microdamage repair, as well as seriously undermines tissue homeostasis causing skeletal fragility 153-156 . Several case reports alerted about the possibility of unusual low-energy subtrochanteric femoral fractures and pelvic insufficiency fractures, often bilateral, refractory to treatment, in patients with history of long term bisphosphonate therapy 157-159 . A local prodromal pain announced some time the subsequent fracture.

Usually radiographic feature showed cortical hypertrophy, a transverse fracture pattern, and medial cortical spiking 160 . A severely compromised bone turnover was detected by histological analysis of tissue involved 161,162 .

The excessive suppression of bone turnover seems to be one of the pathogenetic mechanisms underlying another serious complication associated with long-term bisphosphonates intake, the

Bisphosphonates-Osteonecrosis of the Jaws (B-ONJ).

1.5.1 Bisphosphonates-Osteonecrosis of the Jaws (B-ONJ)

Recently an avascular osteonecrosis of the jaws (B-ONJ) has been characterized as a main side effect of

BP therapy 163-169 .

B-ONJ is defined as a condition characterized by nonhealing exposed bone in the mandible or maxilla persisting for more than 8 weeks in a patient who has taken or is currently taking a bisphosphonate and who has no history of radiation therapy on the jaws 170-173 . It has been suggested that not necessarily the necrotic bone tissue undergoes exposure; therefore the definition has been proposed to be modified as “nonhealing exposed or otherwise necrotic bone in the maxillofacial region” 174 .

This adverse event was first described by Marx and Stern in 2002 175 . The similarity of B-ONJ to cases of phosphorous necrosis of the jaw in workers exposed to white phosphorus (phossy jaw) during the late

19th and early 20th century was reported by Hellstein and Marek 176 and Donaghue 177 .

The tipical clinical appearance of B-ONJ is an ulcerative lesion of the oral mucosa, leaving exposed an area of white-yellowish, obviously necrotic alveolar bone 178 . The surrounding soft tissues often undergo secondary inflammation and infection; mucosal swelling, redness, purulent exudate sometimes with fistula formation are common. Often the patient complains of pain and discomfort in the mouth, bad taste and feeding difficulties 178,179-181 . B-ONJ condition may easily progress to severe

22

forms with intractable pain, inability to eat, severe maxillary sinusitis, oroantral fistula, orbital abscess, extra-oral fistulae, involvement of the lower margin and fracture of the mandible, specially when affects debilitated patients 182,183 .

Indeed B-ONJ has been strongly associated with prolonged use of IV BPs (zoledronate and pamidronate) in cancer patients, while patients affected by non-neoplastic diseases and receiving BPs with lower dosage or different routes of administration seem to incur more rarely in this adverse event.

The cumulative incidence recorded over the years by case-series, case-control and cohort studies is highly variable, ranging from 0.8 to 12% 165, 184-192 ; in non-cancer patients the incidence is between

0.01 and 0.04%, increasing to 0.09 to 0.34% in case of dento-alveolar surgery, while in patients with a malignancy the rate of spontaneous occurrence is between 0.8 and 1.15 %, rising to 6.67% - 9.1% when invasive dental procedures are performed.

This difference in prevalence between the two classes of patients is partially justified by the route of administration, which implies a greater bioavailability of the drug (95% for IV administration compared to 5% for oral intake) and much higher (on average 12 times) doses. Ffurthermore, the role played in promoting B-ONJ by certain conditions commonly observed in patients with cancer, such as comorbidity (blood disorders, anemia, coagulopathy) and multiple pharmacological treatments

(anticancer drugs, immunosuppressants, corticosteroids), should be considered.

The preferred site is the mandible, especially at the mylohyoid ridge. The upper jaw is less frequently involved, although sometimes bilateral or multifocal lesions can be seen in this area. Mandibular tori, exostoses, and in general, the irregularities of the alveolar bone crest are sites with increased risk, because they easily run into mucosal fenestrations due to functional trauma or prosthetic decubitus.

The regional distribution of B-ONJ lesions, limited to the jaws, can be explained by several considerations. A selective concentration of BPs drugs at the interface between active osteoclast and bone-resorption surface has been reported 179 . Jaw bones show a very high turnover rate, many times greater than that of long bones. Therefore the periodontal and alveolar bone surfaces of mandible and maxilla are sites of high BPs uptake and accumulation 15 . Furthermore some special features characterize this skeletal segment from a biomechanical and micro-environmental point of view, as the presence of teeth makes it constantly stimulated by occlusal loading, and jaw bones are separated only by a thin layer of mucosa from the oral cavity, colonized by several bacterial species.

Often osteonecrosis is related to the removal of one or more teeth, to others invasive procedures (i.e. periodontal surgery, dental implant placement, endodontic surgery) or to local risk factors such as

23

periodontal disease 193 . B-ONJ can also occur spontaneously, without any apparent dental disease, treatment, or trauma 178 .

The pathogenic mechanism of B-ONJ is not completely explained. The most accepted hypothesis is an overly suppressed osteoclast function.

In normal bone homeostasis turn-over is essential to repare physiologic microdamage. Long-term BPs intake seems to inhibit bone turnover to an extent that local microdamage is allowed to persist and accumulate. The result is hypodynamic, aged bone with decreased functional competence. Osteocytes run into cell senescence and death, leaving empty lacunae and a hard, brittle bone with an osteopetrotic appearance. This could ultimately lead to bone necrosis, triggered by events such as invasive procedures, inflammation from odontogenic infections or just functional demand by mechanical loading 194 . Not always the triggering event can be identified, and in these cases the onsed is considered to be spontaneous.

In a Beagle animal model, daily oral administration of Alendronate for 1 to 3 years resulted in mandibulatr histopathologic changes and development of necrotic areas in the bone matrix, although no bone exposure presented in any of these animals 195 . To search for a deeper understanding of the

BPs effect on bone metabolism, several animal models have been developed 196,197 . Bi et al.

197 used a mouse model of BONJ-like disease. An equivalent clinical regimen as human myeloma patients was established inducing a murine BONJ-like disease that shared with human B-ONJ the most common clinical and histopathological features such us sclerotic bone, sequestra, bone tissue hypoperfusion and suppressed angiogenesis, impaired wound healing following tooth extraction. The authors were able to uniquely identify in the long-term administration of BPs the causative agent responsible for the onset of the B-ONJ-like disease, while immunosuppressive and chemotherapy drugs were shown to increase the severity of condition, especially impairing soft tissue integrity, in agree with previous findings 198,199 . In this murine model, mechanical trauma due to invasive dental procedures was the primary triggering factor. Guarneri et al.

200 in this regard emphasize that preventing the need for dentoalveolar surgery is the the more correct approach irrespective of chemotherapeutic agents administration, often strictly required to control growth and spread of cancer.

The oversuppression of bone turnover caused by prolonged BPs uptake could allow the persistence of a damaged tissue, unable to withstand the demand for renewal and likely to show full-blown necrosis in presence of trigger factors or simply when such a concentration is reached in bone tissue enough to cause organ toxicity.

24

Specific, bisphosphonate-related inflammatory bony and soft tissue changes prodromal to necrosis have been reported in a further animal model where no other predisposing factors, such as administration of steroids or dental interventions, were present 196 . The fact that only some animals developed B-ONJ raises the issue that individual genetic polymorphism affecting drug uptake and bone turnover, as well as inflammatory and immune response may increase susceptibility or resistance of the subject to the B-ONJ. A candidate genetic trait is polymorphism for matrix metalloproteinase 2

(MMP2) that seems to be related with both skeletal abnormalities and atrial fibrillation 201 .

Nevertheless, at the state of knowledge, nor the study of genetic traits, neither that of laboratory tests have definitively identified a prognostic factor so significantly related to B-ONJ, to predict with reasonable certainty its occurrence in the individual case.

Actually, until now, the biological markers proposed as useful in quantifying the specific risk of B-ONJ onset in the single patient, have not been validated. The serum assay of C-terminal telopeptide of type

I collagen (CTX) has been proposed by Marx et al.

202 as a risk predictor for developing B-ONJ. Reduced levels of this marker appeared to be associated with inactive bone remodeling, and increased risk for

B-ONJ onset, in case of invasive procedures. A relationship between serum CTX and number and size of the lesions, in case of established diagnosis of B-ONJ, has also been reported 203 . According to these observations, it has been suggested that decisions about dental treatment plan and timing, as well as choice of the best time to face B-ONJ surgery, may be taken on the basis of serum CTX levels. It is noteworthy that other authors have not confirmed these findings 204,205 and these recommendations are derived from clinical observations, not validated by well-designed prospective and controlled clinical trials 206, 207 .

As the typical clinical feature of B-ONJ is a dehiscence of the soft tissue leaving uncovered a region of maxillary or mandibular bone, it has been suggested that the initial event in the development of necrosis may be a soft tissue injury 208 . High concentrations of BPs achieved in high turnover alveoloar sites are supposed to cause toxicity of the overlying oral epithelium. The oral mucosa becomes inflamed, and ulcerates causing bone exposure and superinfection. The inability of soft tissues to repair any surgical or traumatic injury could explain the reason why the surgical wound of bone resection often does not heal, and why other drugs that act on bone metabolism do not induce the same lesions.

25

2. Content of the research

2.1 Background and aim

Although B-ONJ has a quite low prevalence, it is a condition of considerable clinical relevance. At the current state, the lack of risk markers, having high sensitivity and specificity for necrosis occurrence, the possibility of progression to severe forms with extended lesions and severe symptoms, the negative conditioning on the patient’s quality of life and the uncertain prognosis, even when proper treatment is performed, make B-ONJ a clinical concern that needs attention by the involved medical community.

Particularly, since the first reports focused on B-ONJ 163 , dental surgical procedures have frequently been described as triggering factors. It is well-known that B-ONJ can develop with dentoalveolar surgery intervention, and tooth extraction appeared to be the main precipitating risk factor, as it is seen in up to 65% of reported cases 209 .

On the other hand, the presence of odontogenic infections exposes patients to considerable risk of B-

ONJ occurrence. Particularly cancer patients exposed to IV bisphosphonates with a history of inflammatory dental disease showed a 7-fold increased risk of developing B-ONJ 173 . In fact, many of the cases reported as “spontaneous”, because an obvious triggering factor could not be identified, may rather have been the result of a not detected odontogenic focus.

From this point of view an absolute contraindication to tooth extraction in BPs patients may not be advisable. Conservative, endodontic, and periodontal non invasive treatments remain the first choice to prevent and resolve odontogenic local infections, specially in patients currently or previously treated with BPs. Nevertheless “hopeless” nonrestorable teeth should be scheduled for extraction also in patients already exposed to medication, specially when their presence prevents the possibility of proper prosthetic rehabilitation or predisposes to infective conditions.

Furthermore some inflammatory conditions, such as localized severe chronic periodontitis or extensive periapical lesions from unsuccessful endodontic treatment, not always can be effectively and timely addressed by means of elective dental therapies, exposing patient to time-consuming and ineffective dental treatments. This situation in subjects scheduled for pharmacological therapy who urgently need to start BPs administration for bone malignancies or severe metabolic bone diseases should be avoided, and teeth with poor prognosis or at high risk of infectious complications should be addressed to extraction.

26

The aim of this research was to retrospectively evaluate the clinical outcomes of patients with past, present or planned BF-exposure, treated with oral surgery procedures in order to prevent B-ONJ; moreover, a clinical report of tot cases of B-ONJ treated with an integrated approach was presented.

2.2 Materials and methods

At Odontostomatologic and Maxillofacial Sciences Department of “Sapienza” University of Rome a task-force of clinicians and researchers set up a Council for Research on Osteonecrosis of Maxillary and

Mandibular bone (“Coordinamento di Ricerca per la prevenzione e la terapia dell’Osteonecrosi

Mascellare” : CROMa). The council consists of a multidisciplinary expert group with thorough knowledge of basic and clinical bone biology as well as expertise and daily practice in the fields of preventive dentistry, oral pathology, operative dentistry, oral and maxillo-facial surgery. The aim of

CROMa is to prevent or treat established B-ONJ and to give relevant informations and advices both to patients and to BPs prescribing providers. The task force joins several expertises in order to provide a comprehensive patient-centered oral care delivery.

An unified clinical chart was developed in order to collect all available data of patients with past, present or planned BPs-exposure in a computerized clinical database. Age, gender, presence of systemic diseases, and use of any drug were registered. Patients were asked for a comprehensive history concerning the use, dose, frequency, and duration of therapy with BPs. Table 5 gives an overview of the data gathered through CROMa clinical chart.

Table 5 – Form to collect and transfer data to electronic database of CROMa

27

Oral health status was assessed and the presence of jaws pathological or anatomical conditions acting as potential B-ONJ risk factors or the finding of full-blown osteonecrosis were recorded thorough physical examination.

For all patients, in addition to anamnestic notes and clinical features, laboratory tests and radiographic data such as ortopantomographs and full periodontal radiographic exams, were harvested and examined.

Asymptomatic patients who did not show B-ONJ, on the basis of all systemical and local B-ONJ risk factors until then identified, were listed according to universally accepted Risk Class and addressed to the most appropriate dental treatment algorithm (Table 6). No bone turnover biomarkers were used, as judged not completely reliable in predicting risk. current

Table 6– Risk class definition and dental care algorithms for BPs Patients

Therapy planned

Route of administration oral intravenous

Risk factors* present absent present absent

Risk class

0

0

0

0

Drug discontinuation and waiting time

------------

Dental treatment

All nonrestorable teeth predisposing to inflammatory or infective condition should be removed, and other necessary surgical dental procedures performed before starting treatment with BPs. Optimal oral health status and high standard of oral hygiene must be achieved. If systemic conditions permit, BPs therapy shoul be delayed until 14-21 days after dental extractions, or until adequate mucosal healing of surgical sites. past oral intravenous oral

BPs therapy < 3 years, no RF

- BPs therapy < 3 years + corticosteroid intake or other systemic RF

- BPs therapy > 3 years ± corticosteroid intake or other systemic RF present absent

< 3 years

II

III

I

I to be considered in consultation with the treating physician not recommended: short-term discontinuation doesn’t benefit, and exposes patient to the risk of

SREs a waiting period is not strictly necessary

All necessary dental procedures, including surgery.

Dental implants can be placed but an informed consent should be provided and patient has to be placed on a regular recall schedule.

Only unavoidable surgical procedures.

Discontinuation of BP for at least 3 months before oral surgery, if systemic conditions permit. BP should not be restarted until extraction sites has healed.

All surgical procedures should be avoided

All necessary dental procedures intravenous

> 3 years

< 1 year

> 1 year

II

III

III if oral conditions permit, wait at least three months after the last administration if oral conditions permit, wait at least six months after the last administration

*

local risk factors: anatomical and/or patological; systemic risk factors: comorbidities and co-therapies

Only unavoidable surgical procedures

28

In case of suspected B-ONJ all necessary data to complete and confirm diagnosis were requested, such as Computed Tomography (CT) scans, magnetic resonance imaging and further laboratory tests, as needed. From a clinical point of view, B-ONJ was defined as exposed, or otherwise necrotic bone 174

(Colella G 2009i) in the maxillofacial region that had persisted for more than 8 weeks, in a patient not previously irradiated in the head and neck district. Lesions were staged according to Mehrotra and

Ruggiero 210 (Mehrotra, Ruggiero 2006), as summarized in Table 7.

I

II

III

Table 7 – Staging of B-ONJ according to Mehrotra & Ruggiero 210

Stage Clinical Manifestation

Exposed bone and asymptomatic

No soft tissue infection

Exposed bone and associated pain/swelling

Soft tissue or bone infection +/-

Pathological fracture and exposed bone

Soft tissue infection not manageable with antibiotics.

Full-blown B-ONJs were treated with an integrated care pathway including medical, biostimulating and/or surgical approach. The most rational treatment algorithm was chosen in each case, on the basis of staging system and matching treatment options available in literature, as summarized in Table 8.

29

Table 8 – Therapeutic options for B-ONJ according to clinical stage

Therapeutic options medical therapy surgical therapy long-term perioperative antibiotic regimen local anesthetic without epinephrine

Platelet Rich Plasma

(PRP) application laser biostimulation ozone therapy

- Broad spectrum antibiotics in case of pain, swelling and suppuration

- Targeted antibiotics in the presence of sensitivity testing antifungal oral medications if swab is positive local or systemic analgesics if pain antiseptics (chlorhexidine)

0.12% mouthwash rinse for 60

"+ gel 0.2% topical application

3 times / day removal of necrotic fragments that hurt overlying soft tissues with hand tools or piezosurgery sequestered bone removal through access flap and hand tools or piezosurgery, achieving primary wound closure resection of the affected bone by piezosurgery, achieving primary wound closure marginal or segmental resection of the affected jaw, with reconstructive procedure if needed

Low Level Laser Therapy

10’ x 2/week repeatable, as needed stage I

Exposed asymptomatic bone staging ref stage II

Exposed bone, with associated pain/swelling/infection

● stage III extensive lesion with complications

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

2.3 Technical procedures

All asymptomatic non B-ONJ patients, with past, current or planned BPs therapy, received oral hygiene care and instructions and – if needed - conservative treatment in order to remove or prevent maxillary or mandibular infection sites.

30

Hopeless teeth, being potential or actual infection sites, were treated with single, multiple or surgical dental extractions.

Surgical extractions in patients exposed to BPs were performed by 3 skilled oral surgeons (SA, RP, IB) with a standardized technique including antibacterial prophylaxis with amoxicillin-clavulanate, perioperative mouth disinfection with chlorhexidine gluconate 0,20% and local anaesthesia with mepivacaine 3 % without epinephrine. Tooth extractions were performed atraumatically so as to limit compression and possible ischemic damage of the alveolar socket walls. Multirooted teeth were removed after sectioning, with a high-speed hand piece and a tungsten carbide surgical burr; luxation and avulsion were gently performed using suitable periotomes, elevators and dental forceps. An ultrasonic surgical device (PiezoSurgery ® , Mectron s.p.a., Italy) was used if alveolar bone surgery was needed; the extraction socket was carefully debrided and curetted in order to remove all granulation and infected tissues; non phlogogenic sutures were used. (4-0 VICRYL, ETHICON LTD, UK). Surgical protocol for tooth extraction is summarized in Table 9.

Tab 9 - Tooth extraction protocol

• antibacterial prophylaxis with amoxi-clavulanate (double dose 1h before surgery)

• mouth disinfection with perioperative chlorhexidine gluconate 0,20%

• local anaesthesia with mepivacaine 3 % without epinephrine

• sectioning of multirooted teeth

• atraumatical extraction using periotomes, root elevators and forceps

• piezosurgery® in case of ostectomy and/or osteoplasty

• 4-0 VICRYL suture

Patients affected by B-ONJ were asked to discontinue BP drug, after consulting with the treating physician. Surgery was performed about three months after drug discontinuation. Patients were scheduled for perioperative ozone therapy sessions (10’ x 2/week x 4 weeks before and after surgery) to improve mucosal trophism and accelerate wound healing.

Patients received 1 g amoxicillin and clavulanic acid (Augmentin, GlaxoSmithKline, Verona, Italy), or

500 mg of clarithromycin (Klacid, Abbott, Abbott Park, Illinois, USA) if penicillin allergy was present, twice a day for 2 weeks before and 2 weeks after surgery; the day of surgery perioral skin antisepsis was achieved with 0.5% chlorhexidine gluconate (Clorexan, IMS, Pomezia, Italy), while preoperative disinfection of the surgical site was carried out with 0.2% chlorhexidine digluconate (Corsodyl, Glaxo-

SmithKline, Brentford, Middlesex, UK), which patients continued as mouthrinse twice a day for

2 weeks to maintain wound disinfection. Local or general anaesthesia was chosen according to site and extent of bone involvement.

31

Surgery included the elevation of a mucoperiosteal flap, removal of granulation tissue, removal of necrotic bone and revision of the residual cavity with manual or ultrasonic surgical devices. In the bone wound was applied autologous platelet gel (platelet rich plasma, PRP) obtained from the patient's own blood by centrifugation, the day before surgery. Horizontal mattress sutures were used to approximate the inside surfaces of the two opposing wound margins, and a second line of closure was obtained by simple interrupted sutures (4-0 VICRYL®, ETHICON LTD ,UK), achieving a tension-free primary closure.

Surgical protocol for B-ONJ treatment is summarized in Table 10.

Tab 10 – B-ONJ surgical protocol

• antibiotic treatment with amoxi-clavulanate (15 days before and 15 days after surgery)

• mouth disinfection with perioperative chlorhexidine gluconate 0,20%

• general or local anaesthesia with mepivacaine 3 % without epinephrine

• sequestrectomy and surgical debridement with piezosurgery®

• platelet-rich plasma application

• 4-0 VICRYL suture

• ozone therapy to improve mucosal healing: 10’ x 2/week x 4 weeks before and after surgery

2.4 Results

Two hundred eighty-eight patients addressed CROMa in the period from January 2009 to October

2011. A progressively greater number of patients addressed CROMa in this period, with an increasing ratio between the total number of patients and that of patients sent by a specialist as a preventive measure, before starting therapy (Fig 2). The main characteristics of the study population are detailed in Figg 3-5.

Two hundred sixteen females (mean age 70±15) and 38 males (mean age 71±8 years) for the group of adults, as well as 18 females and 17 males (mean age 17±14 years) for the group of young patients with dysplastic bone diseases, were visited by CROMa specialists. A total of 225 patients were affected by metabolic bone diseases: postmenopausal osteoporosis (167), osteopenia (11), secondary osteoporosis (6), arthrosis/arthritis (3), cleidocranial dysplasia (1) , osteogenesis imperfecta (35), fibrous dysplasia (2).

Among the 63 patients affected by a primary or metastatic bone malignancy, 9 patients were affected by multiple myeloma, 12 by prostate cancer, 17 by mammary cancer, 8 by renal cell carcinoma, 8 by

32

pulmonary cancer, 3 by chronic lymphoid leukemia, 2 by pancreatic carcinoma, 1 by nasopharyngeal carcinoma, 1 by hepatocellular carcinoma, 1 by endocrine carcinoma, 1 by bladder cancer (Fig tot).

Fig 2

Inflow trend of patients to CROMa

Fig 3

160

140

120

100

80

60

40

20

0

170

160

150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

2008 first half

2009 second half 2009 first half

2010

patients sent by specialist patients who contacted CROMa

Specific pathology requiring BPs therapy for CROMa patients

17

9

3

12

8 8 2 4 metastatic cancer postmenopausal osteoporosis arthrosis/arthriris fibrous dysplasia cleidocranial dysplasia multiple myeloma chronic lymphocytic leukemia renal cancer pancreatic cancer second half 2010

167 first half

2011

3

11

6 2 1 osteopenia osteogenesis imperfecta prostate cancer other malignancies

35 second half 2011 metabolic bone disease secondary osteoporosis mammary carcinoma pulmonary cancer

33

With regard to drug exposure, 101 patients had received or had to receive intravenous therapy, 142 had taken the drug orally, 37 by intramuscular injection and 8 patients had taken different medications by various routes of administration.

Forty-eight patients were sent from the phisician prescriber of BPs to perform dental treatments before starting intravenous (46), oraL (1), or intramuscular (1) therapy. All other patients addressed

CROMa after starting BPs intake.

Fig 4

100

BPs exposure for CROMa patients

intravenous oral

80

60

40 intramuscular associations

20

0 intravenous oral intramuscular associations current

33

87

21

3 past

22

54

15

5 planned

46

1

1

Most patients (181, 96.8 %) with oral or intramuscular exposure, at the first examination showed risk factors local (177 patients, 94.6%), systemic (110 patients, 58.8%), or both (99 patients, 52.9%t). The most frequently detected local risk factors were the poor oral hygiene (63 patients, 33.7%), the presence of untreated odontogenic infections (65 patients, 34.8%) or both (23 patients, 12.3%).

With regard to patients with intravenous current or planned BPs therapy, affected by primary or metastatic bone lesions (63 patients, 62.4%) or by dysplastic bone diseases with juvenile onset such as osteogenesis imperfecta or fibrous dysplasia (37 patients, 36.6%), they were all referred to CROMa by

34

the specialist who treated them for the underlying disease. Five patients receiving intravenous BPs for severe osteoporosis, addressed CROMa spontaneously, for a routine examination or needing for urgent dental care, not referred by any physician.

The most commonly prescribed drugs were oral alendronate in patients with osteoporosis (86 patients, 51.5 %) and intravenous zoledronic acid in cancer patients (60 patients, 95.2%).

Fig 5

Active principles and routes of administration

90

80

70

60

50

40

30

20

10

0 intravenous oral intramuscular alendronate clodronate ibandronate neridronate risedronate

86

2

1

35

4

16

35

7

51 zoledronic acid

60 intravenous oral intramuscular

Ninety-seven patients, not requiring dental extractions, were treated with professional hygiene and conservative dentistry procedures, as needed, and then scheduled for regular follow-ups.

One hundred sixty-nine patients showing hopeless teeth, being potential or actual infection sites, were treated with single, multiple or surgical dental extractions, according to clinical needs (Fig 6).

35

Fig 6

Risk class 0: planned therapy

Risk class I: <3 years, no

RF

Risk class II:< 3 years+RF,

>3 years

Risk class III: intravenous therapy

Performed dental treatments

50

40

30

20

10

0

Risk class 0: planned therapy

Risk class I: <3 years, no RF

Risk class II:< 3 years+RF, >3 years

Risk class III: intravenous therapy single extraction

4

15

24

4 multiple extraction

7

16

27

12 surgical extraction

(one or more)

14

21

18

7

B-ONJ treatment

3

10

9 other non surgical therapy

23

35

22

17

A total of 241 extractions were performed, including 33 incisors, 22 canines, 65 premolars and 121 molars. Extractions involved upper (121, 50.2%,) and lower (120, 49.8%) jaws (Fig 7).

Fig 7

Maxilla

20

15

10

5

0

Right surgical extraction extraction

Left

3M 2M 1M 2P 1P C LI CI CI LI C 1P 2P 1M 2M 3M

Mandible

20

15

10

5

0

Right surgical extraction extraction

Left

3M 2M 1M 2P 1P C LI CI CI LI C 1P 2P 1M 2M 3M

36

No intraoperative complications occurred. All patients returned after 3 days for a check, after 7 days to remove sutures, and on the fourteenth day after surgery to control the soft tissue closure.

Tot patients reported mild postoperative pain in the days after surgery, resolved with the use of nonsteroidal antiinflammatory drugs. After the fourteen-day examination, patients were instructed to contact the CROMa surgeon to report any signs or symptoms on the treated area. Then, all patients were scheduled for six-monthly clinical checks. No patient showed signs or symptoms of B-ONJ during a mean follow up of 12.9±8.4 months.

Twenty-two patients addressed CROMa with an established diagnosis of maxillary, mandibular or multiple-sites B-ONJ, for a total number of 24 affected sites. They were treated with medical therapy in combination with surgical and / or bio-stimulating approach.

In some cases an history of dentoalveolar invasive procedures, or the presence of local risk factors could be identified as a possible reason of occurrence; other cases were reported as apparently spontaneous (Fig 8,9). Stage III B-ONJ cases were reported only for patients belonging to Risk class III, while stage II and stage I lesions were reported in both risk classes I and II, regardless (Fig. 10).

Fig 8

8; 35%

B-ONJ-involved sites in CROMa patients

1; 4%

14; 61% mandible maxilla both

Fig 9

10; 42%

Reason for B-ONJ occurrence

1; 4%

11; 46% tooth extraction local RF spontaneous

2; 8% implant placement

37

Fig 10

Risk class and staging for B-ONJ cases treated by CROMa

6

5

4

3

2

1

Risk class I

Risk class II

Risk class III

0 stage I stage II stage III

Risk class I 2 2

Risk class II 6 4 1

Risk class III 3 3 3

B-ONJ were treated in an integrated medical and surgical and / or bio-stimulating techniques such as ozone therapy or low level laser-therapy (LLL-T). Some cases were treated only with LLL-T, in order to reduce lesion size and symptoms, when surgical approach did not seem sufficiently predictable (Fig

11).

Fig 11

Staging and performed therapy for B-ONJ cases treated by

5

CROMa

medical therapy medical + surgical therapy

4

3

2

1

0 medical + surgical + biostimulating therapy (ozone/L-LLT) stage I

1

3

1

1 stage II

1

2

4 stage III

1

2

2 medical + L-LLT 4 2 1

38

Fig 12

6; 25%

4; 17%

Clinical results

clinical healing reduced lesion size symptoms improvement

14; 58%

All patients showed great clinical improvement, with reduction of the lesions size and reduced symptoms. Several patients (58%) appeared clinically healed, with intact mucosa and no signs of inflammation at a mean follow-up of 42 ± 18 months (Fig 12).

Characteristics of B-ONJ patient, treatments, clinical outcomes and follow-up times are detailed in table 11.

39

Table 11 - Main characteristics of the B-ONJ patients treated by CROMa

Patients

ML

AM

BN

DM

MG

UF

A

S

DL

LB

P

B

C

MS

RR

T

L

Z

C

G

FL

LA age

68

70

70

80

78

75

52

56

81

63

72

72

78

68

76

70

75

81

67

70

78

65 gender

F

F

F

F

F

F

F

M

M

F

F underlying disease osteoporosis osteoporosis osteoporosis

Paget’s disease osteoporosis osteoporosis

BPs therapy alendronate, 3 years alendronate, 4 years alendronate, 4 years clodronate,

9 years alendronate, 10 years alendronate, 11 months osteoporosis alendronate, 2 years mammary cancer zoledronic acid 48 months osteoporosis ibandronate 35 months multiple myeloma zoledronic acid 14 months prostate cancer zoledronic acid 9 months multiple myeloma zoledronic acid 36 months multiple myeloma zoledronic acid 40 months pulmonary cancer alendronate 36 months osteoporosis alendronate 60 months multiple myeloma zoledronic acid 36 months osteoporosis prostate cancer alendronate 24 months zoledronic acid 20 months osteoporosis risedronate 24 months mammary cancer zoledronic acid 10 months osteoporosis alendronate 5 years mammary cancer zometa 16 months lesion site mandible maxilla mandible

- left maxilla (lesion I)

- right maxilla (lesion

II) maxilla mandible maxilla maxilla (lesion I) mandible (lesion II) maxilla mandible mandible mandible mandible mandible mandible mandible mandible mandible mandible mandible maxilla maxilla clinical stage stage II stage II stage I stage I stage I stage II stage II stage I stage III stage I stage II stage II stage I stage II stage II stage I stage I stage II stage III stage I stage I stage III stage III assumed reason dental extraction dental extraction spontaneous spontaneous spontaneous dental extraction implant placement dental extraction spontaneous spontaneous dental extraction dental extraction local risk factors spontaneous spontaneous dental extraction spontaneous de3ntal extraction dental extraction spontaneous dental extraction local risk factors dental extraction spontaneous treatment medical + surgical medical + surgical mediical + sur medical + surgical+ PRP clinical outcomes healing healing healing healing healing medical + surgical + PRP + ozone medical + surgical + PRP + ozone

L-LLT surgical +

L-LLT

L-LLT medical + surgical + PRP + ozone medical

L-LLT

L-LLT

L-LLT medical surgical surgical + L-LLT surgical

L-LLT surgical + L-LLT medical + ozone medical healing healing reduced size reduced size reduced size healing healing reduced size healing symptoms improvement reduced size reduced size healing healing healing symptoms improvement healing symptoms improvement symptoms improvement

40

2.5 Discussion

The CROMa task force was created with the primary intent to be a benchmark for dental patients exposed to the BP drugs or about to take it. Meticulous collection of personal, epidemiological and clinical data, has provided a fairly complete overview of the population exposed to the drug who presented to CROMa. The specific pathologies requiring BPs therapy, the drugs most frequently administered, the level of awareness of concerns related to BPs intake, the presence of local or systemic additional risk factors were recorded and related to clinical outcomes after dental treatment, in terms of prevention and treatment of B-ONJ. Epidemiological data obtained from

CROMa database are available in Figg 3-5. Interestingly, most of the BPs patients with current or past non-intravenous therapy addressed department of dentistry showing the intention to undergo a routine dental visit, or the need for an emergency dental treatment. These patients showed poor awareness of the clinical concerns associated with BPs intake, and often no information had been provided by the prescribing physician about the possibility of occurrence of

B-ONJ after dento-alveolar surgical procedures.

It is noteworthy that the majority of non-intravenous patients at the first examination showed risk factors local (177 patients, 94.6%), systemic (110, 58.8%) or both (99, patients, 53%). The most frequently detected local risk factors were the poor oral hygiene and the presence of untreated odontogenic infections, often in combination.

Patients with intravenous BPs therapy with bone malignancies or dysplastic bone diseases, such as osteogenesis imperfecta or fibrous dysplasia, showed a greater awareness and understanding of the issue, and were referred to CROMa by the specialist who treated them for the underlying disease. All patients (37, 100 %) in this group were examined before starting intravenous therapy, in order to remove any local risk factor predisposing to B-ONJ occurrence.

Only 4 patients had been subjected to monthly intravenous infusions for the treatment of osteoporosis, and they were completely unaware of the problems associated with their therapy.

The CROMa extraction protocol was applied both to patients taking oral BPs, and to patients receiving intravenous administration, although the latter represented a much smaller sample.

The fact that no necrosis has occurred in patients undergoing extractions, although reassuring, should be interpreted with caution. In fact most patients (121, 71.6%) that addressed CROMa and were undergone to dental extractions were belonging to risk classes I and II, and therefore the clinical results obtained may be considered to have little relevance. It is clear that B-ONJ is more strongly related to intravenous bisphosphonates administration (patients belonging to Risk class

41

III), while in patients affected by metabolic bone diseases, receiving the drug by non-intravenous administration (NIP), a lower risk has been reported 211 . On the other hand, osteoporosis is a major public health problem in all industrialized countries, whose incidence is gradually increased due to population ageing and prolonged life expectancy, as well as oral BPs are the most frequently prescribed drug to treat this condition. In 2005 Alendronate was the 15th most prescribed drug with approximately 18 million prescriptions and the bisphosphonate risedronate was 37th with almost 10 million prescriptions 212 . In the Australian population, Fisher et al.

213 reported the peak annual number of prescriptions for BPs in 2006. Although from 2006 there has been a steady decline in the number of filled prescriptions, still BPs remain the dominant antiosteoporotic drugs.

Therefore, from an epidemiological point of view, the low incidence of B-ONJ in patients taking oral BPs might result in a large number of cases, considering the size of exposed population.

Also noteworthy is the fact that the patient that most commonly addresses to the dentist is that exposed to oral therapy, while a cancer patient receiving intravenous BPs therapy less commonly will contact a private practitioner. From this point of view, estasblishing limits of feasibility for surgical procedures as well as a rational extraction protocol for patients taking non-intravenous

BPs would be of great importance, creating a handy reference for the dental community.

Lodi et al.

214 proposed an extraction protocol aimed at patients with history of at least 3 infusions of intravenous bisphosphonate. Patients underwent 20 days of broad-spectrum antibiotic therapy, three days before to 17 days after surgery; in all cases a full-thickness mucoperiosteal flap was reflected with mesial and distal vertical releasing incisions in order to allow a soft tissue primary closure. No case of B-ONJ were reported by the authors, and this was a very important clinical result with the fact that no discontinuation of BPs therapy was made during oral surgery procedures. Scoletta et al.

215 limits the antibiotic therapy to 6 days, 1 day before to 5 days after surgery, and makes use of autologous platelet gel to promote better wound healing.

In the present study only a 2 grams single dose of amoxicillin clavulanate was administered 1 hour before dental extractions, as prophylaxis of surgical site superinfection. Could be put the objection that infection plays an important role in B-ONJ 216 , and restrict the antibiotic to a single preoperative dose could be an hazard. But it should be emphasized that infection in B-ONJ usually arises from colonization of the exposed bone by oral microflora, when the pathological process has already started. It has been also observed that areas of mucosal dehiscence and bone exposure are particularly susceptible to superinfection by a chronic microbial biofilm, in the context of BPs therapy 217-219 . Nevertheless, histopathological samples of B-ONJ show often a

42

multispecies aspecific microflora, supposedly derived from the spread of pre-existing odontogenic and periodontal infections. L arge proportion of patients affected by B-ONJ has concomitant presence of periodontitis as an additional risk factor 193,209 . Based on these considerations, accurate oral hygiene procedures were performed in the weeks prior to surgery and preoperative antibiotic prophylaxis.

The combination of a β-lactam antibiotic with a β-lactamase inhibitor, such as amoxicillin plus clavulanic acid, is considered to have optimal antimicrobial activity against the most common bacteria involved in odontogenic infections 220 . Antibiotic prophylaxis guidelines state that tissue antibiotic levels should be high during surgical procedure and has been shown that prophylactic administration of antibiotics in the preoperative period can significantly reduces the postoperative wound infection rate, even if ostectomy is requested 221 . The time to peak plasma concentration is approximately 1 hour, and not only parenteral 222 but also oral 223 amoxicillin showed a good absorption in the jaw bones.

Furthermore it is well known that antibiotic prophylaxis should be as short as possible, as long as it is effective 224 . If surgery extends in time or involves a significant tissue damage, another single dose can be administered at the equator of its therapeutic interval 220,225 , but not later than 24 hours after initial administration. A prolonged treatment regimen, although indicated in case of overt infection, it is not recommended as a preventive measure, because it does not reduce the infection rate, increases the risk of adverse drug reactions, and facilitates the emergence of bacterial resistances 226 .

Regarding extraction procedure, in the current study a flap was raised only when a surgical approach was necessary to extract the tooth or to stabilize the surrounding alveolar margins if irregular or sharp, to avoid subsequent injury to the overlying soft tissues. The surgeon never tried a primary wound closure, with the exception of completely impacted teeth. In fact, failure of soft tissue closure following dentoalveolar surgery, as first sign of developing B-ONJ, seems to be related to toxicity of epithelium 227 rather than to missing primary closure of the alveolus surgically obtained. Similarly, primary wound closure does not seem to prevent the risk of subsequent mucous dehiscence nor in dental extractions neither in the surgical treatment of B-ONJ.

If the extraction protocol proposed in this study, applied on larger series, was proven to be adequate in preventing B-ONJ, this would result in a significant benefit for patients. Greater attention to the standard preoperative oral health and hygiene, proper perioperative antisepsis and a more rational timing for drug administration, are virtuous behaviors in favor of patient.

43

Long-term administration of antibiotics and invasive procedures should be kept to a minimum need, especially considering that multiple extractions are preferably divided into several surgical session in order to avoid possible wide areas of necrosis 214 . Not only repeated long-term antibiotic therapy is not recommended as it may induce antibiotic resistance, but also repeated invasive interventions are challenging for the patient and induce significant morbidity.

An important criticism that could be raised about the clinical observations reported in this preliminary study is the small sample size, even for patients belonging to risk class I or II. In a large sample Australian study, the reported incidence rate of B-ONJ after dental extractions ranged between 1 in 296 and 1 in 1,130 extractions in patients exposed to oral drug 192 , and between 1 in

11 and 1 in 15 extractions in patients receiving intravenous. These data have subsequently been confirmed by other studies 228, 229 .

From this point of view, not the protocol validity, but the insufficient sampling of the present study could be the reason why the examined population has not experienced B-ONJ.

The greatest difficulty in attempting to deepen knowledge about a rare adverse event is achieving a sufficiently representative sampling. For an adverse event with an incidence rate of 1 in 100 patients, statistical significant difference in incidence (P value =0.05) could be detected between two groups of treatment or observation only if at least 10,000 patients were recruited in each arm of the study.

Studies of this size are not possible in a single center. It would be desirable to standardize data collection and to bring together different databases on the national territory in order to obtain more detailed informations about the epidemiology of disease and the reliability of possible preventive protocols to be validated in progress.

In the current study it was chosen not to use the CTX test. In the opinion of the authors, until a final validation of the sensitivity, specificity and predictive value of the test has not been obtained, it can not be applied on a large scale in clinical decision making.

Twenty-two patients with established diagnosis of B-ONJ addressed CROMa in the observation period. At the state of knowledge, a specific, evidence-based treatment protocol for B-ONJ has not been established. The low incidence of this pathologic condition would require very large groups of treatment to establish with adequate statistical power if a therapy is more effective than another.

At present, literature provides clinician with only a few indications of possible treatment algorithms through case reports and case series.

44

It is well known that surgical removal of necrotic area may involve the risk of recurrence along the resection margin. This is due to reduced regenerative abilities and bone turnover that make the debrided site unable to react to surgical trauma.

Some evidence exists in support of bio-stimulation techniques, such as Low Level Laser-Therapy

(LLL-T) 230 , alone or aimed to optimize the results of surgery 231, 232 and ozonetherapy 233,234 alone, to improve symptoms and reduce the lesion size 235 , or combined with surgery to promote surgical wound healing and optimize clinical results 236 .

Biostimulation through Low Level Laser Therapy (LLLT) promotes bone formation and repair.

Stimulation of cellular energy metabolism mediated by intracellular chromophores, especially mitochondrial, is able to transform photochemical into metabolic energy 237 . Activation of the respiratory chain, increased production of ATP, cytoplasm alkalinization, increased synthesis of nucleic acids, and finally acceleration of cell division have been reported 238, 239 .

Ozone therapy has antimicrobial and wound-healing properties 240,241 , that result in a synergic therapeutic effect with medical and surgical treatment of B-ONJ 233 .

Both LLL-T and ozone therapy are non-invasive and useful techniques, particularly effective in improving some of the biological aspects that supposedly contribute to ischemic necrosis, such as impaired cellular metabolism and microcirculatory alterations due to endothelial injury and thrombosis of the terminal arterioles and capillaries. The clinical efficacy of these two biostimulation systems may result not only by increased perfusion and oxygenation, but also by increased expression of growth factors, such as VEGF, PDGF and TGF-β, and modulation of their receptor activity, being able to promote enhanced collagen synthesis and fibroblast proliferation 231, 232, 242 .

In the present study, an integrated medical, surgical and bio-stimulating approach was applied.

Furthermore, during surgery, PRP was applied into debrided bony wound in order to increase the local concentration of growth factors and promote tissue regeneration 243-245 .

Most patients experienced complete healing of the lesion, and significant improvement in size and symptoms was reported in all treated subjects, but small sample size and methodological limits of this report preclude drawing any definitive conclusion. Of course, well-designed prospective controlled studies would be needed to verify effectiveness of the individual therapeutic strategies.

45

However, as all current treatments appear to be suboptimal, and no consensus has been reached on completely effective and predictable approach once B-ONJ has developed, the best chances lie in prevention.

The most important goal of CROMa is precisely prevention. Currently, preventive approach is not yet common among prescribers of oral BPs, and only tot patients were referred to CROMa before starting BPs oral therapy. Prevention should be more strongly promoted by sharing knowledge in the involved medical community and establishing a fruitful cooperation with the specialist prescriber of the BP drug, working as a team on behalf of patient.

Another important issue addressed by CROMa is that of data collection. Considering the many unknowns that still exist regarding the epidemiology of B-ONJ, the actual odds ratios of predisposing systemic conditions and local risk factors, the main triggering events, the possible biochemical markers predictive of onset, it would be important to establish standardized data collection forms and shared databases in order to gather as much informations about BPs patients. This could provide a detailed description of the population and allow to process the collected data in the case of B-ONJ onset. Worldwide millions of BF oral therapies have been prescribed, and relatively few B-ONJ cases have been reported. However it should be stressed that the reporting is voluntary, so the health care provider may not have correctly followed the diagnostic criteria of the guidelines (risk of overestimation) or may have failed to diagnose some observed cases (risk of underestimation).

The American manufacturer of Alendronate (Merck,

Whitehouse Station, NY) evaluated the incidence of B-ONJ 0.7 / 100,000 person-years of exposure 246 . This finding was derived by relating the number of suspected cases, that is reported but not confirmed, with the number of Alendronate tablets prescribed from the date of approval of the drug, converted to a number of patients / year. Similarly, other studies 192,247-249 that focused on the risk of developing B-ONJ in BPs patients, however praiseworthy, present methodological challenges for accurate data reporting, due to use of data extracted from medical claims 249 , postal surveys 192 databases not specifically created for the purpose and/or based on voluntary case reports 247 , not precise case definition with specific ICD codes 248 .

Finally, patients on intravenous therapy are best monitored by the specialist that manages their underlying disease; furthermore, in case of B-ONJ onset the more severe lesions associated with intravenous bisphosphonates are often managed at institutions that regularly report to the health National Registers and to the

Pharmacovigilance system using ICD codes, while it is possible that several cases of less severe

46

lesions associated with oral BPs intake, are managed by non-institutional dentists who tend not to report the adverse event.

CROMa uses an electronic system of data collection that allows statistical analysis of the collected informations, and that, if adopted in several centers, and if a considerable number of patients was reached, it could provide a more accurate epidemiological picture of the BPs patient population and the true incidence of B-ONJ.

Of course an agreement should be reached nationwide on the more rational way of collecting data and a largely approved database should be shared between the main institutions dealing with the issue.

2.6 Conclusions

Although B-ONJ is a relatively rare side effect of BPs therapy, it is still an important issue for the medical community due to the severity of the condition and the lack of a thorough understanding of the pathogenetic mechanisms. Precisely the low incidence of B-ONJ is a particular feature which limits the possibilities for study and analysis of this disease.

In the study of B-ONJ, as rare pathologic condition, clinicians and researchers meet objective difficulties in defining pathophysiology and predisposing risk factors. Also current clinical recommendations result from case reports, retrospective case series and expert opinions. An accurate delineation of the pathogenic mechanisms at the cellular and biochemical levels, is not yet available, but necessary to reach clinical and laboratory endpoints for accurate diagnosis and prediction of B-ONJ susceptibility.

Some elements regarding the pathogenesis of B-ONJ have been clarified, but much remains to be investigated about the pathogenic puzzle, the predisposition of the single subject to develop this adverse event, the dental treatments that can be performed without risk or with appropriate riskbenefit ratio, the possibilities for treatment in case of overt disease. To this end might be useful to create large databases and perform multi-center observational studies, in order to reach the power of statistical significance in testing the correlation between occurrence and risk factors as well as the effectiveness of preventive and therapeutic protocols. It is important that the involved medical community share knowledge, and that the phisicians prescribers of the drug take a conscious attitute in order to provide patients with the highest quality of oral health care, before starting BPs therapy.

47

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111. Watts NB, Diab DL. Long-term use of - Padis

Bisphosphonates use and oral surgery : prevention and treatment of the

Bisphosphonates-related Osteonecrosis of the Jaw

Inflow trend of patients to CROMa

patients sent by specialist patients who contacted CROMa

BPs exposure for CROMa patients

Active principles and routes of administration

Performed dental treatments

B-ONJ-involved sites in CROMa patients

Reason for B-ONJ occurrence

Risk class and staging for B-ONJ cases treated by CROMa

Staging and performed therapy for B-ONJ cases treated by

CROMa

Clinical results

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111. Watts NB, Diab DL. Long-term use of - Padis

Bisphosphonates use and oral surgery : prevention and treatment of the

Bisphosphonates-related Osteonecrosis of the Jaw

Inflow trend of patients to CROMa

patients sent by specialist patients who contacted CROMa

BPs exposure for CROMa patients

Active principles and routes of administration

Performed dental treatments

B-ONJ-involved sites in CROMa patients

Reason for B-ONJ occurrence

Risk class and staging for B-ONJ cases treated by CROMa

Staging and performed therapy for B-ONJ cases treated by

CROMa

Clinical results

Related documents

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