A review of the EMAS clinical guide: Selective oestrogen receptor modulators for postmenopausal osteoporosis

In  Europe,  osteoporotic  fractures account  for  more  Disability  Adjusted  Life  Years  (DALYs)  lost than common cancers with the exception of lung cancer. The economic  burden  is  considerable  and  it  has  been  estimated  that  the direct  cost of osteoporotic fractures in Europe is about EURO  36  billion.

Osteoporosis is defined by the World Health Organisation (WHO) as a bone mineral density that is 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by DEXA.

Various  therapies  such  as  bisphosphonates,  strontium  ranelate and  more  recently  enomsumab  are  available.  However  concerns  have  been  raised  regarding  safety  such  as  oesophageal  cancer, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures with bisphosphonates and venous thromboembolism with strontium ranelate.

Santiago Palacios from Madrid, Spain and colleagues recently produced a clinical guide on the  evidence  for  the  clinical  use  of  selective  oestrogen  modulators (SERMs)  in  the  management  of  osteoporosis  in  postmenopausal  women.1

In the guide the authors explained that SERMs  are  chemically  diverse  compounds  that  lack  the  steroid structure  of  oestrogens,  but  interact  with  oestrogen  receptors  (ERS) as  agonists  or  antagonists  depending  on  the  target  tissue.  The agonist and antagonist properties of SERMs derive from differentially expressed ERS, ligand-dependent receptor conformational changes, interactions with various co-activators and co-repressors expressed and recruited in different tissues, and subsequent changes in gene transcription.  Differential  gene  regulation  with different  SERMs  ultimately  contributes  to  the  different  cell- and-tissue-specific  activities  of  SERMs. The early SERMs such as tamoxifen, toremifine and raloxifene, were originally developed  for  the  prevention  and  treatment  of  breast cancer and were subsequently found to conserve bone mass.  Two new SERMs, bazedoxifene and lasofoxifene, are now licensed in Europe. Bazedoxifene  (BZA)  is  a third-generation  SERM, developed  for  the  prevention  and  treatment  of  postmenopausal osteoporosis.

 

Bazedoxifene  (BZA) 

In a  pivotal  phase  III  clinical  study  to  evaluate  the  effectiveness  and  safety  of  BZA  in  preventing  fractures in  postmenopausal  women  with  osteoporosis  (55–85  years  of age). Participants received daily treatment of BZA 20mg(n = 1,886)  or  40mg  (n = 1872),  Raloxifene (RLX)  60mg  (n = 1849)  or  placebo (n = 1.885),  as  well  as  a  daily  supplement  of  1200  mg  calcium  and 400–800  IU  of  vitamin  D.  Among  6,847  subjects  in  the  intent-to-treat  population,  the  incidence  of  new  vertebral  fractures  was significantly  lower  (p  <  0.05)  with  bazedoxifene  20  mg  (2.3%),  bazedoxifene  40  mg  (2.5%),  and  raloxifene  60  mg  (2.3%)  compared with placebo (4.1%), with relative  risk reductions of 42%, 37%, and  42%,  respectively.  The  treatment  effect  was  similar  among subjects  with  or  without  prevalent  vertebral  fracture  (p  =  0.89 for  treatment  by  baseline  fracture  status  interaction).  The incidence of non-vertebral fractures with bazedoxifene or  raloxifene was  not  significantly  different  from  placebo.  In  a  post  hoc  analysis  of  a  subgroup  of  women  at  higher  fracture  risk  (femoral neck T-score ≤ −3.0  and/or  ≥1  moderate  or  severe  vertebral  fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene20mg showed a 50% and 44% reduction in non vertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60mg (p = 0.05),respectively. The 2-year extension included a total of 4,216 women providing 5 year data .  The  raloxifene  arm  was  discontinued  after 3  years;  subjects  receiving  bazedoxifene  40mg  were  transitioned  to bazedoxifene 20mg after 4 years. Five-year findings were reported for bazedoxifene 20 and 40/20mg cohorts and placebo. At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was significantly lower with bazedoxifene 20mg (4.5%)and  40/20  mg  (3.9%)  versus  placebo  (6.8%;  p  <  0.05),  with  relative  risk  reductions  of  35%  and  40%,  respectively.  Non-vertebral fracture incidence was  similar  among  groups.  In a  subgroup  of higher-risk women (n = 1324; femoral neck T-score ≤ −3.0 and/or≥1  moderate  or  severe  or  ≥2  mild  vertebral  fracture[s]),  bazedoxifene 20mg reduced non-vertebral fracture risk versus placebo (37%;  p  =  0.06);  combined  data  for  bazedoxifene  20  and  40/20mg reached  statistical  significance  (34%  reduction;  p  <  0.05).  After 7-years continuing  benefit  on  vertebral  fracture  risk  was  still found.

The number of reported cardiac disorders and cerebrovascular events was equally low among all treatment groups up to 7 years. While the general occurrence of pulmonary embolism and  retinal  vein  thrombosis  was  increased  in  the  treatment groups  compared  to  placebo,  this  was  not  statistically  significant.  However  the  risk  of  deep  vein  thrombosis  was  significantly  increased  after  3  years  (RR  8  (CI,  1.01–64.25)). The SPC* for bazedoxifene also mentions a “description of selected adverse reactions: In the osteoporosis treatment trial in 7,492 evaluable subjects (mean age=66 years), the bazedoxifene-treated women had an increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism and retinal vein thrombosis).”

After 3, 5 and 7 years, there were no differences in breast cancer incidence between the different groups. The authors concluded that BZA has demonstrated a favourable endometrial  profile  over  5  years  of  therapy.

 

Lasofoxifene

Lasofoxifene** is a  naphthalene  derivative,  third-generation  SERMs with  better  oral  bioavailability  than  other  compounds,  and,  was developed  for  osteoporosis  prevention  and  treatment  in  post-menopausal women.

The pivotal Lasofoxifene  (PEARL) trial randomized 8,556 women aged 59–80 with  a  BMD  T  score  of  −2.5  or  less  at  the  femoral  neck  or spine, to receive a daily dose of lasofoxifene (0.25mg or 0.5 mg) or placebo  for 5  years.  Lasofoxifene  at  a  dose  of  0.5mg/day,  as  compared with  placebo,  was  associated  with  reduced  risks  of  vertebral  fracture  (13.1  cases  vs.  22.4  cases  per  1,000  person-years;  hazard  ratio, 0.58;  95%  confidence  interval  [CI],  0.47–0.70),  nonvertebral  fracture (18.7 vs. 24.5 cases per 1,000 person-years; hazard ratio, 0.76; 95% CI,  0.64–0.91).  Lasofoxifene  administration  was  associated  with  significant  reductions  in  ER-positive  breast  cancer  (0.3  vs.  1.7  cases per  1,000  person-years;  hazard  ratio,  0.19;  95%  CI,  0.07–0.56),  coronary heart disease events (5.1 vs. 7.5 cases per 1,000 person-years; hazard  ratio,  0.68;  95%  CI,  0.50–0.93),  and  stroke  (2.5  vs.  3.9  cases per  1000  person-years;  hazard  ratio,  0.64;  95%  CI,  0.41–0.99). Lasofoxifene at a dose of 0.25mg/day, as compared with placebo, was associated with reduced risks  of  vertebral  fracture  (16.0  vs.  22.4 cases  per  1,000  person-years;  hazard  ratio,  0.69;  95%  CI,  0.57–0.83) and  stroke  (2.4  vs.  3.9 cases  per  1,000  person-years;  hazard  ratio,0.61; 95% CI, 0.39–0.96).

Both  the  lower  and  higher  doses,  as  compared  with  placebo, were associated with an increase in venous thromboembolic events (3.8  and  2.9  cases  vs.  1.4  cases  per  1000  person-years;  hazard  ratios, 2.67  [95%  CI,  1.55–4.58]  and  2.06  [95%  CI,  1.17–3.60],  respectively), but  there  was  no  evidence  of  an  increase  in  the  incidence  of  pulmonary embolism.

In the conclusion the authors pointed out that the  EMA  approved an indication  for  BZA  in  the  treatment  of  osteoporosis  in  postmenopausal  women  at  increased  risk  of  fracture.  These  new  SERMs  points  to  a  greater  anti-fracture  potential  than raloxifene  with  positive  breast,  endometrium,  coronary  heart  disease and stroke safety profiles over seven years. Currently BZA is available  in  Spain,  Switzerland,  Italy,  Ireland  and  Japan  and  it  is anticipated  will  be  launched  soon  in  other  countries. Lasofoxifene  was  approved  in  Europe  in  2009  for  the  treatment  of osteoporosis in postmenopausal women at increased risk of fracture.  FDA (Food  and  Drug  administration)  approval  has  not  been granted.  Safety  findings  noted  by  the  FDA  included  increased  incidence of uterine diagnostic procedures, increased incidence of VTE, and  a  small,  but  significant  increase  in  all-cause  mortality  with  the 0.25mg,  but  not  the  0.5mg,  dose. The  decision,  of  when  to  begin  and  what  type  of  treatment  to  use, should be based on the need to reduce fracture risk. All treatments including  SERMS  should  include  recommendations  for  a  healthy  life style  and  adequate  calcium  and  vitamin  D  intake.  Additional benefits of  different  agents  (i.e. climacteric symptom  improvement  with oestrogens, breast cancer prevention for SERMs) must be considered when selecting the most suitable anti-osteoporosis drug. Furthermore what agent  is  used  (oestrogen,  SERM,  bisphosphonates)  may  vary  over  a woman’s life time.

This review is a summary of the paper published by Santiago Palacios and colleagues.

Reference: Palacios  S,  et  al.  EMAS clinical guide:  Selective  oestrogen  receptor  modulators  for  postmenopausal  osteoporosis. Maturitas (2011), doi:10.1016/j.maturitas.2011.11.01

 

*SPC for Bazedoxifene from www.Medicines.ie on 19 April 2012

 

**Lasofoxifene –  please note that this product is not yet approved for use in Ireland