Healthspanlife - the Official Life! Blog

Ross & Henderson’s sentinel (JAMA 1980) paper on the strong relationship between long term oral premarin  total dose and breast cancer was  largely ignored:  that  with cumulative premarin dose >1,500 mg (ie 7yrs) the breast cancer  risk  was estimated to be 2.5 in women with ovaries (vs  0,7 sans ovaries); the risk ratio for a high cumulative dose (ie after about 15years, >3mg premarin)  rose to 5.7 relative to nonusers with normal breasts.

But at the same time, Finnish papers in Maturitas showed why, because of non-physiological high E1>E2 even on oral E2,  systemic ERT is preferred:

Punnonen R ea: (in E2V 2mg/d  & the Renin-Aldost system: 1980:2:91-4) that  “on oral E2v the E2 levels rose to normal and (unlike  on oral premarin, EE2) caused  no rise In BP, aldost, renin; they thus preferred such natural  ERT which does not activate the biliary, RAS renin-angiotensin system, and thrombosis”;

 but Heinonen  PK et al (1982:4: 273-6 Estrogen levels on oral E2) showed that  on E2v  4mg/d orally, blood   E2 rose 5X and  E1 rose 25X; so they recommended avoiding   oral ERT.

Thus the Womens’ Health Initiative confirmed three facts: 

1. starting OHT well after age 60yrs and continuing even modest dose cyclic  (premarin 0.625mg plus MPA 5mg) does more harm than good; THIS SAYS NOTHING ABOUT APPROPRIATE PHYSIOLOGICAL BALANCED COMBINED PARENTERAL TESTOSTERONE-PROGESTERONE-ESTRADIOL HRT FROM ANY POSTMENOPAUSAL AGE HAVING ANY  LIFELONG RISKS WHATSOEVER.

2. starting the same OHT regime soon after menopause - especially premarin alone- reduces  all major diseases and mortality by about a third, except for rare cases of deep vein thrombosis and cholelithiasis;  this outcome was confirmed in the 9year RCT in Finland (Heikkinen ea 2006) in which women on oral estradiol 1mg/d +- MPA 2.5mg from menopause had zero major adverse events.  BUT THIS SPEAKS ONLY FOR AT MOST THE 9 YEARS THAT  THESE WOMEN WERE IN THE TRIALS.

There are  so far some seven  major functional types of steroid hormones  in humans: calciferols; androgens; estrogens; progestins; glucocorticoids; mineralocorticoids; and  endogenous digitalis- natriuretic hormone (eg Goldstein  2006, Weidemann 2005; Kurup ea 2003) .

     Apart from  gender-reproduction-childhood growth promotion (ie androgens, estrogens & progestins), their actions fall into many other systemic classes; which in conventional “replacement” doses  the literature and experience suggests may be compared as follows:

+=increase;    - = lessen; n = apparently neutral?  AS=anabolic steroids.

The active hydroxycalciferols are in a sense exocrine ie are produced from ingested  vitamin D3 and cholesterol in the skin and kidneys, not from dedicated endocrine glands; but while their synthesis needs no more than an hour of sunlight a week in sunny climates, and modest kidney function, calciferol deficiency is increasingly recognized in those who take little dairy products, and little sunshine. Thus the pituitary, skin,  parathyroids, adrenals  and  gonads are the primary  endocrine glands of growth.

The other steroid hormones (like the other major anabolic hormones- insulin and human growth hormone HGH) are endocrine ie are vulnerable to both intrinsic endocrine failure (Hypothalamic-Pituitary-Adrenal- pancreatic-Gonadal ),  and to  endocrine gland decrease and blockage by infections, cancer, major stress, auto-antibodies or direct trauma.

       All these anabolic  hormones  if swallowed are destroyed  by digestion/  1^st-pass hepatic metabolism; thus to achieve the same systemic effect,   comparative doses are reported as follows:                 

The vulnerability  of oral steroid therapy is illustrated by oral contraception: where taking eg an oral antibiotic can compete for absorption, reducing   blood SH levels so that accidental conception occurs. Similarly, a postmenopausal  patient with rheumatoid arthritis, on oral (E+P HRT), reports that  her analgesic  requirements  rise while she is on antibiotics.

     One  needs to go back to a standard textbook of Pharmacology of  1958, (Kranz & Carr: Pharmacological Principles of Medical Practice: Balliere, London) to find the corollary:  eg “cortisone acetate implant, or im  2-5mg daily injection as replacement for  Addisons’ Syndrome”: “For menopausal symptoms, combined E+TT is often employed…”;  “oral synthetic estrogens (have replaced natural ones due to availability,  oral form & lower cost; but) produce undesirable: nausea, cramps, migraine and male breasts.    Estrogen + TT are additive, and E doses may therefore be reduced   since the combination gives smoother transition:  73% of patients remain  symptom free.    TT 10mg imi 3 x/week may control  functional uterine bleeding better than progesterone”!.

      It is widely overlooked that  TT is converted irreversibly by aromatase to E2 in the tissues; but   giving E2 does not do the reverse – it  suppresses the  HPAG and   TT production. Thus women need to be given TT with estrogen, but  men do not need to be given estrogen -  giving them TT increases their E2 levels by about 1/3. This source of E2 may not be enough for balance in women, but reduces their needed dose of administered estrogen;  hence in women  on a standard 20:1 TT:E2  injection combination, or on combined implants eg TT 50mg + E2  20mg/6months,  the blood TT level should be monitored to check that the mean TT is in the physiological range of  1-3.5nmol/L, but the E2 level need  not be above perhaps 0.1nmol/L – in fact, to avoid excess fat deposition and breast cancer stimulation, it must  not , since TT is supplying E2 direct in target organs.

     Hence Ginsberg J & Prevelic GM  at Royal Free Medical School  ( Drug Therapy & Reproductive Endocrinology: London: Arnold 1996) note that in BRCA, androgen + prednisone give good results;  they advise: parenteral> oral ERT: eg  E2 patch 50u/d;  or Implants eg TT 50mg + 20mg E2 /6mo (= 300mcg TT + 110mcg E2/ day)..

In TOPICS IN O & G 1998: (ed Julian Bassin: Julmar Communications, Jbg 4^th Ed 1998: sponsored by all the RSA gyne Drug Suppliers):  Schnitzler CM wrote that “ERT should be given for life, from as early as possible, but even from 80yrs; the elderly not exposed to the sun needing >2000u vit D/day. Sonnendeker on HRT wrote that oral  HRT raises both coagulation & renin substrates acutely; EE2 should not be used for ERT; thus he prefers oral ERT except  if coagulopathy, liver/biliary/ triglyceride/ or vascular headache  problems, when he uses non-oral ERT. Indications for androgens are: poor libido; persistent tiredness & OP; preferring the 25mg TT pellet to oral androgens or imi esters”.

Finally, the physiological logic of parenteral  (as opposed to oral) HRT- in this case sex hormone replacement) was already well recognized and marketed over 60 years ago – even in South Africa- in eg the handbook Sex Endocrinology (Schering, New Jersey, 1944) which recommended and listed creams, injections and implants as well as tablets.

William Masters and colleagues followed this up with the first apparent RCT of HRT published in 1953,  who showing  in a 13month titration RCT that biweekly ie shortacting  esters  imi TT 20mg  + E2 1mg    (= T ~2.8mg/d + E2 ~0.14mg/d, ie a ratio of 20:1 to 22:1 – as in Schering’s Primodian Depot or Organon’s Mixogen)  restored 70% of geriatric women in their mid70s to selfcare; allowing the nursing staff on the unit to be halved. Overall the women had ~one brief menstrual bleed  after about 5weeks, thereafter on follow-up biopsy all maintained endometrial atrophy. Some  needed initial T:E dose titration (between eg 30:1 to 15:1)  for individual variation in response. As a result  both Schering and Organon to this day sell this preparation as a 100mg TT ester + 5mg estradiol ester ial, to be given as desired every 3 – 6 weeks.

     We have found for the past  ~10 years that, just as hypogonadal men do optimally  on about 200mg depotrone subcutaneously sc  every fortnight (= 10mg TT a day), women do well on  Masters’  20:1  TT:E2 hormone ratio, the optimal regime being on average 0.2ml 20mg of hormones by domestic  subcutaneous selfinjection every 2 weeks ie TT 1mg/day and E2  0.05mg/day,  – the average resultant  blood levels being TT round 2.5nmol/L - but of course the testosterone itself delivering far more estradiol extra- and intracellularly.

  With this regime we have never seen a breakthrough bleed in postmenopausal women, for the simple reason that follow-up endometrial ultrasound uniformly shows endometrial atrophy. We have also never seen increasing changes on follow-up screening mammography since it is common cause that testosterone suppresses female glandular breast proliferation.  

These  results with arenteral HRT  have been abundantly confirmed in women followed for up to  40years on parenteral HRT by leading menopause clinics such as Greenblat  & Ganbrell(Augusta); Gelfand(Montreal); Schiff(Boston), Buster(Houston), Notelovitz (Florida), Vliet(Tucson), Lichten(Michigan), Shippen(Philadelphia), Karpas(Atlanta); Schleyer-Saunders, Whitehead and Studd(London UK); Tvedegard Moller & Hansen(Copenhagen); Burger & Davis, Zhou & Dimitrikakis (Australia); and our Cape Town group under Davey;

and

most important of all:  since longterm trials beyond the necessary critical 20 years  will never be carried out in humans due to the cost, the results of primate studies by Thomas Clarkson ea at Wake  Forrest University  showing  that starting even oral premarin at castration in young  female monkeys and continuing it for the human equivalent of 15 years blocked onset of atheromatous disease ; but premarin alone or with MPA  produced breast proliferation;  but like endometrial proliferation, this was suppressed by testosterone replacement.

       The greatest myth (if not drug industry  hoax) of the past 30 years may be the claim that postmenopausal women (or for that matter women needing contraception) need a patent estrogen and a synthetic progestin for endometrial  and breast protection and contraception; when it was shown decades ago that depot estradiol plus depot progesterone- or better still,  depot estradiol plus depot  testosterone plus depot progesterone - do best for both contraception and HRT  and all-system protection against all the degenerative diseases of aging. 

The fevent hope and effort  of the patent designer drug industry is that they can buy off enough practitioners, academics, researchers, Regulators and politicians so that the widespread avilability, low cost - and massive all-disease prevention- of such natural supplements as human hormones as well as the dozens of other proven biologicals including vitamins and mineral is never appreciated and utiized. They cannot curb their insatiable lust   for immediate endless profits no matter how much suffering it causes - disaster capitalsm- by recognizing that if they now promote such safe cheap proven panaceas to both the poor and the prosperous consumers, they will extend healthspan by decades, producing far more survivors who will later rather than sooner still need/want to buy their designer products.

4. to follow: THE IMPORTANCE OF THE SITE OF PARENTERAL INJECTIONS

DOES THE SOURCE,  MEASUREMENT, DOSE, BALANCE, and  ROUTE OF ADMINISTRATION OF SEX HORMONE THERAPY HRT MATTER?

Chapter 

1.      THE IMPORTANCE OF THE MEASUREMENT OF BLOOD LEVELS OF SEX HORMONES

          While urologists,  andrologists and internists  demand blood hormone  levels to diagnose male hypogonadism ,  adrenal, thyroid  or other endocrine dysfunction ,  many gynecologists still apparently  give postmenopausal HRT without ever measuring levels.

           Do baseline and achieved sex hormone levels matter ?

           Older authorities(mostly male or trained by men) did not believe so; hence we still see women presenting  on  eg implants or Premarin up to 2,5mg/day for years, with Estrogen  levels of well above 3nmol/L ->10 times what is necessary and safe),  or SHBG levels well over 200nmol/L; some of them grossly bloated and dysfunctional if not with mushrooming breast cancers or  the obesity metabolic syndrome.

      The textbook HORMONE REPLACEMENT THERAPY HRT (A Wayne  Meikle ed: Humana Press, USA  1999: p266) says  in Men’s Sex Hormone Replacement SHR: “the  general principle of SHR  is to normalize the (TT) level”.  “The safe course is to duplicate normal physiology as much as possible:  HRT  should allow self-administration, be convenient, affordable, minimal discomfort, with predictable responses. TT-cypionate  or TT-enanthate  100mg/week maintains physiological levels between 16-32 ie mean 24nmol/L.   Mixtures of short-and-long-acting TT  (eg Sustanon) are  thus  not recommended”.

At p412 Davis & Burger, for TT Replacement  in women, say:  “replace TT levels to at least the UPPER level of  normal physiological range for young ovulating women”.

     Meikle’s  authoritative  Textbook thus stresses the importance of  duplicating  normal human  physiology .  This  requires  using human systemic (ie not oral) hormones which can  and  must  be measured before and periodically on SHR -

 ie  using only systemic TT in men, systemic TT + E2 + Progesterone in women.

The 2000 Management of the Menopause Millenium Review (Studd JW ea, London) strongly promotes measuring hormone levels and balance in both sexes: ”calcium loss decreases with serum E2> 72pmol/L; vasomotor symptoms at >126-252pmol/L; and lipids changes at  250pmol/L- whereas breast cancer BRCA cells responds  to  E2>36pmol/L”  but does not say how these interact with TT levels;  so it is  important to monitor the serum E2, to keep it in the therapeutic window above about 100 but below 250pmol/L ie mean about 200pmol/l;  many women do not feel better on solo ERT – so few persist  on it; Studd ea  thus recommend “E2 patch rather than orally, for less hypertension, gallstones, DVT & hepatic protein formation.”      “it  is mandatory to measure BMI and % body fat;   the single best screen for Insulin resistance is a  fasting glucose/insulin(G:I) ratio below 4,5.

       “Depression is the commonest functional disorder of aging men, in whom aging sexhormone changes - PEDAM(Partial Endocrine  Deficiency of Aging  Men)-  include falling androgens, rise in SHBG, arteriosclerosis  & CVD,  and decrease in brain hormones & wellbeing – with especially decrease in melotonin & sleep, muscle strength, RBC, cognition, bone,  immunocompetence,  &  erection.”

       The Johannesburg gynecologist editor of Wyeth’s Menopause Update August 2001 certainly advocates frequent E2 measurements to titrate the frequency and dose of E2 implants, “aiming for a blood level of 0.35-0.45nmol/L: side effects occur when the dose exceeds the patient’s needs”.  Kopenhager in the same issue promotes “lowdose ERT – 1mg/day oral E2 causing less side-effects like headache, swelling or mastalgia, without increase in body mass”; but he overlooks the fact that 0.05ug of E2/day systemically will often suffice, that body weight says nothing about the steady gain in fatmass and loss in muscle  mass with aging and unopposed estrogen.   Prof  Frank Guidozzi from Johannesburg in the same issue makes the  point about TT replacement even for men – 250mg ester/ fortnight intramuscularly ie  a mean 12mg TT/day, or 5mg/day by patch, or 120mg undecanoate/day orally..

          As Fritz Schumaker said, there is a need for the right amount of  all things, from water to air.  A bit too little or a bit too much food, insulin or cortisone will be seen and felt fairly soon; whereas with thyroid, vitamin D and the sex steroids it may take months to years before it becomes apparent – when it may be too late, with broken marriage, spirits, heart or bones, or cancer.  Optimal doses, blood levels and balance  are apparent throughout nature and  for all hormones – with balance between the hormones – between the strengthening androgens and the fattening estrogenics – being the most important to balance the bloodpressure and lipids, thrombosis and bruising, fat-mass and lean-mass,  concrete and intuitive skills,  hypo-and hyper-immunity,  apathy and drive.  

            Well-published clinical studies for 80 years since hormone measurements began (McLeod  & Banting; Albright; Dubois, Masters, Bulbring, Hayward, Stoll, Mackay,  Wang, Henderson, Greenblatt, Speroff, Vermeulen, Roitt & Delves, Nieschlag & Behre, Motohashi,  Studd, Whitehead, Maartens et al)  have  shown the importance of  titrating doses and measuring  bloodlevels of the superhormone family - estrogens and androgens, cortisone, insulin and thyroid -  in men and women,  on every system, the mind and body.

OPTIMAL SEXHORMONE LEVELS

Sue Davis et al from Monash University  have been eloquent advocates of normalizing female TT levels above the 1.5nmol/L level;  this has been done by eg  Schleyer-Saunders in London, Gelfand and Gambrell in Augusta,  Morrie Gelfand et al at McGill Quebec, and Davey’s group  in Cape Town for over 30 years. There seems to be wide consensus that E2 level should be between 0.1-0.25nmol/L – but bearing in mind that breast cancer increases in proportion to the estrogen dose, and that plasma E2 reflects the (free)  plasma estrogens and androgens only in the presence of normal SHBG and in the absence  of any other estrogenics.

The Healthy TT level in Young Men

      Most seem to take it for granted that, at any adult age, a plasma TT anywhere above the bottom of the population range (eg 10nmol/L) is normal and adequate. Pfizer claims  in it’s Viagra trials that only impotent men with TT below about 8nmol/L were excluded,  since  those with TT level less  than about 2sd or 20% below the lower range of “normal” were not classified as hypogonadal.

Yet this level is 1/4 of the vigorous youthful 35-40nmol/L which we sometimes find in dynamic men even  in their mid-fifties.  Aversa A ea in  Italy (in Clin Endoc 2000:53:517-22) show how Androgens and Erection correlate, that  older  impotent men have  TT  around 13-19, mean 16nmol/L  ie half the level of young men;  those with vascular impotence having 25% higher E2 & SHBG, and  40% lower free TT (only about 45pmol/L,  versus 75pmol/L) than in  the psychogenic group; thus fTT correlates with penile elasticity;  (cf  male TT “normal range” at all age  9-35 ie mean 22nmol/L- whereas eg Greek  recruits at  army intake: mean TT level about 32nmol/L-Mantzoros et al).

        Salmimies’ paper  (1982) already 20 years ago illustrated that there is no sharp cutoff point for impotence, for response to TT:  “15 diverse hypogonadic men received im TTEnanthate (25 to 250 mg TT) or placebo injections 2 weekly, each dose for 4 weeks. All patients with pre treatment plasma TT values below 2 ng/ml(ie <7nmol/L) reported impaired sexual function. In four patients with TT between 2 and 4.5 ng/ml who reported impairment, TTE 50 to 250mg successfully improved rated sexual behaviour. Four matched men with TT level in the same 2 - 4.5ng/ml range reported high erectile function that did not change with TT E inj. These data indicate that male sexual behaviour is impaired at an individual plasma TT below between 2.0 and 4.5 ng/ml “       ie : the range of erectile loss or response is at least between 7 and 16nmol/L on their assay.

But did they, does anyone,  give enough TT, achieve adequate blood levels for long enough in non-responders?

     Andy  Guay’s 2001 abstract  illustrates the same point, there is a (?semilog) linear response ; (as  is  seen eg in Gilbert Forbes’  1980’s elegant demonstration of the semilog linear response between total TT dose and lean body mass over years). In Guay’s 44 patients (apparently 50-70yrs old) studied in detail, altho 14.9pg/ml is in the lowest quintile of the “normal” fTT range, there was 100% response to Viagra. Drop the fTT 30% and the response fell 25%; drop the fTT 45% from 14.9 to 8.1 and the response drops 84%; drop the fTT 50% to 7.4 and the response drops by 91%.

      This predictable dose response curve correlates with the finding in wasting AIDS, (Rabkins’ and Wagner’s,  Bhasin’s, and Grinspoon’s groups), that some sick men with AIDS wasting do not become anabolic at 100mg TTenanthate/ week but, improve only when the dose is increased to 150 or even 200mg/week imi- ie to a mean TT level of 30 - 40nmol/L. Bhasin’s group in LA was the first to report, in 1995, that in HEALTHY men, modestly superphysiological doses of TT cypionate or enanthate  (eg 200mg/week) (which no more than double normal  TT blood levels to around 60nmol/L,  still below the danger level of 80nmol)  improve muscle mass and strength by 10-20%; and correspondingly in frail elderly – without adverse effect.

      Thus it is  obvious that there is no arbitrary TT bloodlevel cutoff point above which Viagra is justified de novo before trial of TT replacement. Since there are no absolute contraindications to physiological systemic human TT replacement [except untreated (prostate or breast) cancer]; and since there are no risks of such measured replacement except with untreated frank heart-failure, jaundice or untreated cancer, the phosphodiesterase inhibitors  PDI (with risk of sudden death) are never justified (at a local cost of about >US$130/month) until weekly subcutaneous gluteal selfinjection of depot TT has been tried for a few months at a cost of about US$3 to $5/month.

Our own search  a few years ago (Burman, Bornman ea)  traced over 73  published reports of studies which give TT levels in groups of  “normal” men  the past 40 years; of which about 64 reports measured TT levels in men below 39 years of age. Four  were longitudinal studies in such young men, amongst about 38 longitudinal and cross-sectional studies.  Bearing in mind Klee and Vermeulen’s recent conclusions (2000-2001) that laboratory method (RIA) has changed little the past 40 years and that all reliable measures (TT, fTT, bioavailable TT etc) correlate fairly well,  our plots confirm that  mean male TT level falls about 0.7% per year (range 0.2% to 2%pa) between youth and old age ie about 40% over 50years;  but that in healthy lean  young men under 39years, the mean TT level has remained about 24nmol/L(+-16%) for 40 years; in the 22 studies between 1958 & 1985, the range was 16-35nmol/L-mean 25; in the 42 studies since 1987, the range was 14-40nmol/L-mean 27nm; – Bornman’s Pretoria series(in young men admitted for voluntary sterilization) understandably  yielding the lowest testosterone means…

          But these figures belie that  while TT falls modestly, the TT/(E2XSHBG) product  falls drastically since both E2 and SHBG rise with aging, especially with disease: eg values may change  from  youthful (TT) 25X(SHBG norm) 20/(E2: 0.1X measured SHBG:20) = 250;  to  an aging man’s     15X20/(0.15X30)   = 66; ie the TT/E2 product has fallen by 75%.

Chapter 2 follows soon.

It’s tragicomedy that the BBC – the quintessential British spokespersona – laments NHS woes: * UK c.diff deaths ‘rising sharply’ * “The equivalent of one person an hour dies in hospital from clostridium difficile, figures suggest.”

And yet Authorities there and mostwhere are still in denial about enforcing simple safe low-cost multi-system prevention – in this instance to keep people out of bed and hospital, off antibiotics.
Authorities- regulators, politicians, the Tax Man – benefit as hugely from disease as do their fairy godmother the Disease Industry- the Drug conglomerates and their researchers and lobbyists, private hospitals, medical schemes - that pay them handsomely and creates myriad factories and jobs.

So because it is not profitable, Prevention Does Not Pay, no matter that it adds decades to health:

*There is no move to ban smoking, to make it (and sale, and allowance thereof) a criminal offence.

*No move to immediately jail drunken drivers for a long time, and on second offence permanently confiscate their driving licence and ban them permanently from current and future public office and public vehicle driving, be they judges or janitors, cabinet ministers or cabbies.

*The banning of deadly polluting coal-and oil-powered vehicles and major electricity sources has been blocked for decades by the endlessly greedy and ruthless oil-based industry magnates, despite the fact that these finite energy sources are desperately needed for other purposes. Now the world faces immediate famine because the oil-based transport-and energy behemoths (who have blocked investment in natural – solar - energy for decades) are paying bigger dollars for crop and marine resources as energy supplies than most consumers can afford to pay for these finite resources as food.

*No official move to acknowledge that the best drugs for both prevention and chronic treatment are the long-proven natural low-cost vigorous safe daily doses of a few score appropriate micronutrient supplements - vitamins (~15), minerals(~10) and biologicals (human and other species’) that are increasingly inadequate in the food chain in longer-lived increasingly overweight stressed humans facing worsening man-made epidemics and environmental disaster.

*No serious move yet by the US FDA- the chief protector of the new drugs industry of the west -English- Europe- Japan – (against the interests of consumers) to enforce integrity, insist that no chronic designer drugs for the chronic major common degenerative diseases be released for general use until they have been proven both at least as safe and effective as those already existing and effective, in major randomised controlled trials of a mean of at least 8years, head to head against both older designer drugs, and long-proven natural drugs, for similar purpose, in those diseases.

*The past decade alone has seen condemnation of myriad unproven unnecessary and risky released drugs –
on Wikipedia alone at least a dozen - eg Propulsid; cerivastatin; Vioxx; pemoline; benzbromarone; torcetrapib; and the discrediting of the non-steroidal anti-inflammatory drugs as no better - and potentially more hazardous than- appropriate cortisone and micronutrient use, and
newer designer antidepressants and anticlotting agents as less safe and effective than appropriately used older ones;

*the unnecessary anti-osteoporosis bisphosphonates that are increasingly associated with the very long-bone fractures they are supposed to prevent;

*and most especially the wannabe oral anti-diabetic anti-atheroma and anti-obesity drugs – statins, rimonabant, glitazones, meglitanides and sulphonylureas - as inferior to and less safe than metformin, the 85year old plant extract which is the only designer drug ever proven as invaluable panacea in a 20year RCT, tested against sulphonylureas, but not against all other modern designer drugs which (as in more recent studies) have never been shown to meaningfully reduce all-cause morbidity and mortality as does metformin.

The until-recent FDA haste to licence new drugs after scanty trials was reminiscent of the criminal conspiracy between the FDA and industry that licenced the already contested diethylstilbestrol Chicago trial of 1950- and kept that drug on the market another 25years after it was discredited. And it was in stark contrast to the FDA (to protect USA drug companies) blocking drugs already in highly effective use elsewhere for decades, like lithium carbonate, metformin and betablockers.

Since no drug corporations promote the out-of-patent old and proven agents, authorities cannot afford to promote truth - that the only remedies for chronic prevention that lower all-cause disease and mortality by between a third and a half - overweight, obesity, diabetes, cancer, hypertension, arthritis, osteoporosis fractures, vascular disease, acute infections, depression, dementia - are:

-fish oil a few grams a day- which also drastically lowers behavioural and learning disorders;
-a lowcost simple blend of a few score other proven natural micronutrients - the fifteen vitamins, ten minerals and the human / other species’ biologicals including herbs;
-metformin titrated to tolerance about 2.5gms a day, for both prevention and treatment of overweight, diabetes type 2 and most major chronic degenerative diseases; &
-appropriate conservative balanced sex hormone replacement in most older men and women, as proven in the landmark Womens’ Health Initiative and Finnish Oulu randomised controlled trials, and numerous other studies in major centres in North America, UK, Europe, Australia and South Africa, since 1953.

It is a tenet of endocrinology for the past 60 years that all major hormone deficiencies should be replaced permanently and physiologically with the same human hormones, yet there are still those, even medical specialists, who would deny this to those most in need – from middle age onwards, especially women. At least some of these specialists have the honesty to disclose that they are well paid by drug compnies to be advocates and trialists for the wannabe designer drugs to supplant the old.

Recognition of appropriate measured low cost HRT and the other proven listed supplements for all aging people would of course rob the drug industry of perhaps 90% of it’s market for it’s wannabe designer substitutes that the FDA allows to be marketed prematurely until enough people die of their complications or shortcomings.

In fact, while no study shows that any modern drug for common chronic degenerative disease prevention does any overall - mutidisease- good, reduces all-cause mortality, those who promote and practice such published truth – that the old is better - are threatened with prosecution.

Why is there surprise at the new 4year international study (in NEJM of 3 April 2008 http://content.nejm.org/cgi/content/abstract/358/14/1431 ) that further 26% lowering of average “bad” low density cholesterol LDLC - level (and CRP c-reactive protein) by adding a new designer drug for 2 years to a statin alone makes no further difference to vascular or all-cause outcome? In fact in even this young population there were 46% more cardiovascular CVD events on the statin - ezetimibe combination (10/357 = 1.4%pa) than on simvastatin alone (7/363 = 0.96%pa).

At baseline the subjects at a mean age of 46+- 10yrs (half men) were an average of about 10kg overweight; 28% smoked, only 16.4% were already hypertensive, but 80% already on statins (they had to have had a total cholesterol TC of >5.43mmol/L off lipid-improving drugs – their mean TC off drugs was 10.4mmol). Other than the 5% who had already had heart attack, and perhaps the 2% who were diabetic, why were these average mostly well young people targeted for further cholesterol lowering, when their mean TC was already down to 6.9mmol/L on statin (vs 5.7 on the twin drugs) with HDL 1.2 ? when all they needed to do was lose a few kg fat by sensible eating and exercise, stop smoking and take some safe fat-reducing anti- atheroma antioxidant and insulin-sensitising supplements including fish oil? Why should lowering of blood markers already within the average range give any benefit as opposed to doing harm? According to Sijbrands (BMJ 2001) from Erasmus University http://www.bibalex.org/Supercourse/lecture/lec3191/001.htm, such a cohort of people untreated has a standardized mortality ratio of 1.88- but in this new 2008 Enhance paper, their mortality rate on statin alone was already so low (CVD mortality 0.1%pa) that all-cause mortality was not even mentioned.

So it should be asked why such a trial was undertaken, when there has never been any evidence that drug lowering of mild to moderate TC (ie below 8mmol/L) or LDLC lowers non-CVD morbidity and mortality? – and when there are legion proven supplements that lower morbidity and mortality ? The evidence against cholesterol lowering in those without high CVD risk was already shown over a decade ago by the Sheffield team (Haq 1995), who have consistently stressed that “cholesterol measurement by itself is not a good way to identify those with high coronary risk”, and that there is little advantage (except for anti-cholesterol practitioners and laboratories) in lowering average cholesterol levels unless CVD risk is at least 2% if not 3% a year. The CVD risk of this Enhance trial cohort on statin was only 1% a year.

No statin trial has ever shown that these lipid-lowering drugs drugs lower or even address non-vascular disease or mortality; whereas (except in those at the highest cardiovascular risk) nonvascular degenerative disease is by far the bigger burden in later years. Dr James le Fanu summarised the evidence against universal cholesterol-lowering in mild-to-moderate lipidemia already in The Rise and Fall of Modern Medicine (Abacus UK 1999).

Since according to the lipid-lowering industry, most of us overweight older folk naturally have risky lipid levels to be targeted by zealous drug marketers and prescribers, some British doctors who know better have actually invested heavily in promoting (without evidence of global benefit :risk) a farcial polypill including a statin, an antihypertensive and aspirin for all. http://www.bmj.com/cgi/content/full/326/7404/1419

It is common cause that after 30 years of widespread use, statins do nothing for overweight, insulin resistance, hyperglycemia, other CVD factors, nor for other major degenerative diseases of overweight and aging - infection, osteoporosis, cancer, arthritis, sexual dysfunction - and thus do nothing to lower non-vascular morbidity and mortality. But statins do cause widespread insidious fatigue, myalgia, depression, impotence; and now lung and tendon rupture complications, let alone hepatorenal problems- are being increasingly reported.

By contrast, it is common cause from both trials and observational studies for >30years that APPROPRIATE
1) metformin for overweight/ lipidemia; 2) fish oil; 3) combined hormone replacement; and 4) blend of the other proven >60 supplements (~15 vitamins, ~10 minerals, and the >35 biologicals including herbs), each reduce all-cause morbidity and mortality by one-third to half. Together, the combination is impressively effective in daily practice in the most desperately ill patients already on maximum conventional prescription modern drugs for osteoporosis, arthritis, CVD, type 2 diabetes on insulin with crippling neuropathy etc.

Such is the insidious influence of the global drug industry via Regulators (Elaine Feuer Innocent Casualties: The Fda’s War Against Humanity USA 1996), that we physicians are threatened with prosecution by our own medical defence advisor if we do fair comparative marketing, promote that appropriate well-proven old drugs- the natural micronutrients which drug companies prudently refuse to sponsor to be tested against modern patented prescription drugs - are better for both prevention and treatment of chronic degenerative diseases of aging than the imitator modern wannabe patentable designer drugs that attempt to mimic the original natural drugs- vitamins, minerals, biologicals - evolved and proven over millennia.

We are even threatened with prosecution for using metformin for prevention of diabetes and lipidemia, when it is the only patent drug that has ever been tested in a 20year RCT (Holman ea the UKPDS 1998), and proven to halve all-cause mortality over 5 years in type 2 diabetics, and it halves the incidence of new diabetes in overweight people with metabolic syndrome risks; whereas in trials, sulphonylureas - like all other modern patent designer drugs - had no benefit on all-cause mortality or on decreasing new diabetes incidence in older adults.

Ndb
Refs:

Haq IU, Jackson PR, Ramsay LE ea Royal Hallamshire Hospital, Sheffield, UK Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease. Lancet. 1995;346:1467-71 http://www.ncbi.nlm.nih.gov/pubmed/7490996 and Prediction of coronary risk for primary prevention of coronary heart disease: a comparison of methods QJM. 1999 ;92:379-85. http://qjmed.oxfordjournals.org/cgi/content/abstract/92/7/379

J.P. Kastelein ea, for the ENHANCE Investigators http://content.nejm.org/cgi/content/short/NEJMoa0800742 NEJM 3 Feb 2008: 358:1431-1443 Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia

This new report at http://news.bbc.co.uk/1/hi/health/7319393.stm 1 April 2008 that “Medication ‘worsens Alzheimer’s’ ” confirms the obvious futility of prescription drugs for this condition.
No modern chronic designer drugs give any proven longerm benefit for this disease- at best a brief slowing in progression for a few weeks.

So, as for avoidance of other largely irreversible/incurable disabilities

- sudden death, obesity, stroke, blindness, prostate/breast cancer, and osteoporotic hip/ spine fracture

- it is crucial that every person likely to live well past 60 years take permanent safe low-cost multisystem preventatives from middle age if not younger

- the ~15 vitamins, 10 minerals, and at least 20 of the proven >70 biologicals
[from alphalipoic acid to zeaxanthine - all of them in a powder blend drink twice a day, including fish oil in some form, and appropriate optimal HRT - eg melotonin, thyroid,
and parenteral sex hormone replacement- testosterone for men, testosterone- estradiol - progesterone for women].

this 5year Canadian followup (http://jnci.oxfordjournals.org/cgi/content/abstract/100/4/252) study of women after breast cancer confirms the recent (200 follow-up from Italy about the low mortality from breast cancer detected and treated early (Elderly breast cancer patients treated by conservative surgery alone plus adjuvant tamoxifen: Fifteen-year results of a prospective study. Martelli G, et al National Cancer Institute, Milan, Italy.Cancer. 2008; 112; 3: 481-488).

In UK the annual deathrate for women from breast cancer was only 0.28% http://info.cancerresearchuk.org/cancerstats/types/breast/mortality/
- but in the UK screening program, of 1.7million women screened, 4.8% were recalled for further screening - of whom only 80% had unnecessary screening- a giant burden to both patients and the NHS. Almost 80% fewer mammography procedures and facilities were actually required.

Contrary to the mythology and hype that breast cancer is a major killer of women, these three studies affirm that even in those who get breast cancer, it still kills only 0.5% a year of sufferers at any age, (as opposed to 1% of those over the age of 70yrs in the Italian study)
Thus >80% of truly asymptomatic women without good family history of breast cancer have the lucrative (to Industry) unnecessary regular screening mammography
- and there is no good evidence that in such women, (or men) regular repeat cancer screening makes any difference to survival..

The evidence from numerous sources is very strong, that appropriate supplements ie parenteral HRT (estrogen +testost- +prog-esterone -especially when combined with other natural biologicals eg - fish oil, coQ10, acetylcysteine, MSM, carnitine, arginine, ribose, herbs ; and minerals and vitamins) more than halve all major chronic degenerative diseases and premature deaths.

People who fear cancer and all disease , early disability - especially those with a significant family history- just have to use common sense:
- follow sensible diet and lifestyle including avoiding overweight, have bloodpressure and eye checks regularly,
- take a sensible combination of the >50 natural supplements (if only as a few oil capsules and a glass of powder blend twice a day, and either daily hormone cream (or a tiny
hormone subcut (self) injection every few weeks, or implant, or lowdose HT orally) ; and
- most important of all, report promptly to a doctor if they develop symptoms that do not settle in a few days eg unexplained pain bleeding, lumps or tenderness, swelling, breathlessness, cough, or change in vision, hearing or bowel or bladder habit etc; or persistent weight gain or loss.

If early and permanent supplements; and symptoms, are addressed early, the common major diseases rarely become major killers - we die active of healthy old age!. Without appropriate supplements including appropriate HRT even after breast cancer, all-cause disease and mortality is more than doubled. Waiting for sudden death, diabetes, obesity, blindness, hip fracture, cancer or dementia before starting safe lowcost permanent multi-prevention is truly crippling if not fatal.

How to Survive a Heart Attack When Alone: coughing and deep breathing?
This email doing the rounds may be inappropriate advice that could cost people their lives. - see http://www.hoax-slayer.com/survive-heart-attack.html and http://www.viahealth.org/body_rochester.cfm?id=329

BUT an apparently reputable cardiologist (apparently ex Vietnam Medic) also recommends it: http://www.karinya.com/cpr.htm

BUT see the notes of caution at http://en.wikipedia.org/wiki/Cough_CPR.

In short, it may save those who have sudden arrhythmia- but it is less likely to save those who are having a huge heart attack.- for whom most interventions are too late. The compromise may be to switch on the vehicle’s emergency flicker, stop the car, start coughing while collapsing visible over the steering wheel with a hand on the hooter to attract attention..

Very very few people recover or survive well long term after spontaneous (ie non-violent, non-toxic) cardiac arrest outside hospital - the studies below from France, Germany , USA & UK indicate that successful survival without impairment is - in the best hands - below perhaps 5%. .

So only primary prevention pays. Fish oil halves sudden death; metformin halves the deathrate in type 2 diabetics - and halves new diabetes in the overweight; appropriate estrogen replacement lowers allcause premature mortality by a third; deficiency of testosterone, estradiol, minerals, vitamins, CoQ10 , arginine, carnitine and ribose play a crucial role in the development and reversibility of arrhythmia, cardio/vascular and all-cause degenerative disease; and testosterone is antiarrhythmic but estrogen arrhythmogenic.

By contrast, unlike the above proven life-extenders, no modern designer drugs for chronic use have been shown to significantly reduce all major chronic degenerative diseases and premature all-cause mortality.

Thus all should take natural supplements early and permanently - appropriate vigorous supplements of minerals, vitamins and biologicals (including fish oil, insulin sensitizers and sex hormone replacement), to minimize early vascular disease and arrhythmia potential.

ndb

Heart. 2007 ;93:601-5. Sudden arrhythmic death syndrome SADS : a national survey of sudden unexplained cardiac death.Behr ER, Casey A, Sheppard M, University of London, UK. The estimated mortality from SADS was 0.16/100 000 per annum (95% CI 0.12 to 0.21), compared with an official mortality of 0.10/100 000 per annum for International Classification of Diseases 798.1 (sudden death, cause unknown-instantaneous death) or 1.34/100 000 per annum for unascertained causes of death. CONCLUSIONS: Deaths from SADS occur predominantly in young males. When compared with official mortality, the incidence of SADS may be up to eight times higher than estimated: more than 500 potential SADS cases per annum in England. Families with SADS carry genetic cardiac disease, placing them at risk of further sudden deaths. SADS should therefore be a certifiable cause of death prompting specialised cardiological evaluation of families.

European Heart Journal 2006 27:406-412 Post-discharge survival following pre-hospital cardiopulmonary arrest due to cardiac aetiology: temporal trends and impact of changes in clinical management Jill P. Pell ea University of Glasgow,
The Heartstart Register was used to identify all 1659 patients discharged alive from Scottish hospitals during 1991–01 following pre-hospital arrest due to cardiac aetiology. Over the period studied, the proportion of people suffering pre-hospital arrest who survived to discharge from hospital changed from 11.6% (552/4766) in 1991–93, to 7.0% (558/8006) in 1997–01.

Resuscitation. 2005 65:49-55. Outcome after cardiac arrest: predictive values and limitations of the neuroproteins neuron-specific enolase and protein S-100 and the Glasgow Coma Scale. Pfeifer R, ea University of Jena, Germany.
BACKGROUND AND PURPOSE: Patients resuscitated from cardiac arrest are at risk of subsequent death or poor neurological outcome up to a persistent vegetative state. We investigated the prognostic value of several epidemiological and clinical markers in 97 patients undergoing cardiopulmonary resuscitation (CPR) after non-traumatic cardiac arrest between 1998 and 2002. RESULTS: 72.% of the patients died or remained in a persistent vegetative state; and 28.8% survived with severe, moderate or without neurological disorders. .

N Engl J Med. 1999 341(8):569-75. A comparison of standard cardiopulmonary resuscitation and active compression-decompression resuscitation for out-of-hospital cardiac arrest. French Active Compression-Decompression Cardiopulmonary Resuscitation Study Group.Plaisance P, ea .Lariboisière University Hospital, Paris, France. BACKGROUND: We previously observed that short-term survival after out-of-hospital cardiac arrest was greater with active compression-decompression cardiopulmonary resuscitation (CPR) than with standard CPR. In the current study, we assessed the effects of the active compression-decompression method on one-year survival. METHODS: Patients who had cardiac arrest in France, more than 80 percent of whom had asystole, were assigned to receive either standard CPR (377 patients) or active compression-decompression CPR (373 patients) according to whether their arrest occurred on an even or odd day of the month, respectively. The primary end point was survival at one year. The rate of survival to hospital discharge without neurologic impairment and the neurologic outcome were secondary end points. RESULTS: Both the rate of hospital discharge without neurologic impairment (6 percent vs. 2 percent, P=0.01) and the one-year survival rate (5 percent vs. 2 percent, P=0.03) were significantly higher among patients who received active compression-decompression CPR than among those who received standard CPR.

Chest. 1994 ;106:872-9. Survival after in-hospital cardiopulmonary arrest of noncritically ill patients. A prospective study. Berger R, Kelley M. Veterans Affairs Medical Center, Lexington, KY 40511.
BACKGROUND: The rising healthcare costs and the ethical and economic implications of cardiopulmonary resuscitation (CPR) have generated interest in defining criteria to predict the appropriateness of CPR in specific patients. Age has been proposed as one such a criterion. METHODS: As part of a quality assurance program, all instances of CPR (code-500) at our VA Medical Center were prospectively studied over a period of 45 months. Only events in noncritical care hospital areas were included in this analysis. The CPR data were prospectively collected, and follow-up of initial survivors was continued until the end of the study period or until a patient died. RESULTS: Of a total of 422 code-500 events, 387 (92 percent) met our study definition of cardiorespiratory arrest, and 255 of these occurred in a noncritical care area and were included in the study. Our immediate survival was 52 percent (n = 132), survival after intensive care unit (ICU) stay was 22 percent (n = 55), survival to hospital discharge was 11 percent (n = 28), and 4 percent of the patients (n = 10) were alive at the end of follow-up (mean, 22 months). None of the patients discharged alive had a significant new neurologic deficit, and all but one returned to their preadmission environment. The post-CPR hospital charges for each of the surviving patients was estimated at $63,000. Whether in-hospital CPR in noncritical care areas is cost-effective is an issue that society at large must eventually decide.

Drugs Exp Clin Res. 1992;18:355-65. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Davini P, ea Santa Chiara Hospital,Pisa, Italy. A controlled study was carried out on 160 patients of both sexes (age between 39 and 86 years) discharged from the Cardiology Department of the Santa Chiara Hospital, Pisa, with a diagnosis of recent myocardial infarction. L-carnitine was randomly administered to 81 patients at an oral dose of g 4/die for 12 months, in addition to the pharmacological treatment generally used. For the whole period of 12 months, these patients showed, in comparison with the controls, an improvement in heart rate (p < 0.005), systolic arterial pressure (p < 0.005) and diastolic arterial pressure (NS); a decrease of anginal attacks (p < 0.005), of rhythm disorders (NS) and of clinical signs of impaired myocardial contractility (NS), and a clear improvement in the lipid pattern (p < 0.005). The above changes were accompanied by 90% lower mortality in the treated group (1.2%, p < 0.005), - in the control group mortality was 12.5%. Furthermore, in the control group there was a definite prevalence of deaths caused by reinfarction and sudden death. On the basis of these results, it is concluded that L-carnitine represents an effective treatment in post-infarction ischaemic cardiopathy, since it can improve the clinical evolution of this pathological condition as well as the patient’s quality of life and life expectancy.

Mol Aspects Med. 1994;15 Suppl:s165-75.
Usefulness of coenzyme Q10 in clinical cardiology: a long-term study.Langsjoen H, University of Texas Galveston .
Over an eight year period (1985-1993), we treated 424 patients with various forms of cardiovascular disease by adding coenzyme Q10 (CoQ10) to their medical regimens. Doses of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242 mg). Patients were followed for an average of 17.8 months, with a total accumulation of 632 patient years. Eleven patients were omitted from this study: 10 due to non-compliance and one who experienced nausea. Eighteen deaths occurred during the study period with 10 attributable to cardiac causes.. Of 424 patients, 58 per cent improved by one NYHA class, 28% by two classes and 1.2% by three classes. A statistically significant improvement in myocardial function was documented . Before treatment with CoQ10, most patients were taking from one to five cardiac medications. During this study, overall medication requirements dropped considerably: 43% stopped between one and three drugs. Only 6% of the patients required the addition of one drug. No apparent side effects from CoQ10 treatment were noted other than a single case of transient nausea. In conclusion, CoQ10 is a safe and effective adjunctive treatment for a broad range of cardiovascular diseases, producing gratifying clinical responses while easing the medical and financial burden of multidrug therapy.

Mol Aspects Med. 1994;15 Suppl:s143-7. Coenzyme Q10 and antioxidants in acute myocardial infarction.
Kuklinski B, ea Klinikum Südstadt, Rostock, Germany.
Sixty-one patients admitted with acute myocardial infarction, and a symptom’s duration of less than 6 hr were randomized into two groups. Immediately after hospitalisation, members of the verum group (n = 32) received 500 mcg of selenium (as sodium selenite). Thereafter they received a daily dosage of 100 mg coenzyme Q10 (Bio-Quinone) and 100 mcg selenium (seleno-methionine) for a period of one year. The control group (n = 29) were given matching placebo preparations.. Biochemical parameters showed a reduced concentration of CPK- and ASAT-level in the verum group during the acute phase (although not statistically significant). None of the patients in the verum group (i.e. on antioxidative treatment) showed prolongation of the frequency corrected QT-interval. In the control group, 40% revealed a prolongation of the QT-interval by more than 440 msec (p < 0.001). There were no significant differences, with respect to early complications. During the one-year follow-up period after myocardial infarction, six patients (20%) from the control group died from re-infarction whereas one patient from the verum group suffered a non-cardiac death.

Int J Tissue React. 1990;12(3):163-8. Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme Q10 and conventional therapy. Langsjoen PH, ea Scott and White Clinic, Temple, TX USA.
During 1982-86, 43/137 patients with cardiomyopathy, Classes II, III and IV, had ejection fractions (EF) below 40%, and a mean EF of 25.1 +/- 10.3%. During treatment of these 43 patients with coenzyme Q10 (CoQ10), EF increased to 41.6 +/- 14.3% (p less than 0.001) over a mean period of 3 months (range, 2-4 months). The mean CoQ10 control blood level was 0.85 +/- 0.26 micrograms/ml which increased on treatment to 1.7 to 2.3 micrograms/ml for five periods up to 36 months (each period, p less than 0.001). The survival rates for all 137 patients treated with CoQ10 and for the 43 patients with EF below 40% were both about 75%/46 months. These two survival rates were comparable between 24 and 46 months, which is of extraordinary significance and importance when compared to survival of about 25%/36 months for 182 patients with EF below 46% on conventional therapy without CoQ10. The improved cardiac function and trippled survival show that therapy with CoQ10 is remarkably beneficial due to correction of CoQ10 deficiency in mechanisms of bioenergetics

BONE BOOSTERS? Biphosphonates BNPs NDB 2007 updated 19 March 2008; 6 April 2008

No trials have ever been published showing that biphosphonates do overall good long term for osteoporosis- ie reduce all-cause mortality, and reduce hip fracture, without toxicity.
Biphosphonate Osteonecrosis of long bones was already published in 1995, and from 2001 in USA.
So their heavy marketing, and prescription like vitamins, causing the epidemic of devastating osteonecrosis, makes the prescribers, manufacturers, dispensers and Regulators - eg the FDA -criminally liable.

Effects of continuing ALENDRONATE after 5 years of treatment: Fracture Intervention Extension to 10yrs
JAMA. 2006 Black, Cummings UCSF. (who funds them?!)
In 1099 women re-randomized to alendronate or placebo for a further 5 years (1998-2003):

Continuing alendronate halved only recognized vertebral fracture risk (2.4% vs 5.3% for placebo);

their conclusion: “women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years”. Ie no benefit for the far more important hip bones.

But was this a dangerous lie?
the 19% Risk of nonvertebral fractures was no different (RR 1 ) between continuing and discontinuing alendronate.

“Susan Ott (JCEM Mar 2005) already questioned bisphosphonate long term safety”

Biphosphonate BPN Jaw OSTEONECROSIS ONJ is now endemic worldwide:
1st reported in 1994 (Guanabens, Spain- leg stress #s),
2001-03 - USA 63 cases (Ruggiero 2004)
(2002-5 Pozi) Italy- 35 ;
(2003-5 (Abu-Id 2006) Germany 73 cases
2004-5 (Mavrotoki) Australia 158

by July 2006 over 3000 cases of ONJ were reputedly already reported.

“of Odvina‘s 9 cases of spontaneous fractures on alendronate -
5 were mid-femur fractures (2 bilateral same as Toulouse).
6 had delayed or absent fracture healing.

Estrogen alone is anabolic only on bone, uterus, memory, fat – If anything it both builds inner hostility, fattening, inflammation,
& wastes collagen ie muscle catabolic - thus doubles incontinence.

The only true anabolics (ie strengthen muscle, melt fat) are
* food incl vita-/minerals incl. vitamin C/D; CoQ10, carnitine,
* Insulin sensitizers – metformin; natural androgens, exercise.

Dach: “ Look at Toulouse Lautrec.. His parents were first cousins…
” we are giving women Toulouse Lautrec’s bone disease- the same jaw necrosis, mid-femur fractures, failure of bone healing,

“ But women who sustain fractures on BPNs are told that the fractures are due to the underlying osteoporosis, not the drug”
http://www.drdach.com/wst_page6.html

The osteonecrosis problem may be 95% with iv BPNs (Urade) - orally BNPs like HRT are absorbed below 10%;
but
as with oral HRT, the problem may be both total dose absorbed, and total length of exposure –BPNs (given over perhaps a year iv) bind to bone for 10yrs. Fosamax is swallowed for 3-5yrs.
Jones & Wilkinson’s (April 2006 NHS review of oral BPN adversity) found that adherence on oral BPNs is only around 50% by 3 years due to adversity – GIT, musculoskeletal, skin….
and when stopped, BMD is maintained for up to 2 yrs due to bound Testosterone (unlike estrogen).

Is there (as there was with tobacco, Premarin & Vioxx)
a BMD industry OSTEOPOROSIS FRACTURE DECEPTION?

The OSTEOPOROSIS FRACTURE DECEPTION?:

The chief risk factor for fractures is not BMD, osteoporosis,

but immobility, falls, inco-ordination, muscular frailty = sarcopenia
– which in turn limits exercise, endurance, motivation.

By contrast,
permanent appropriate TRT in men and T+ E2RT in women can prevent eg the up to 40% bone loss that occurs in 6 months on corticosteroids (Studd 1989),

restore up to 26% of lost BMD in critical areas like Ward’s triangle ie (the hipbone’s neck);

of the 6 published RCTs that have given testosterone replacement (with or without estrogen) for 1-2 years post menopause, 5 showed that testosterone gave better increase in BMD than estrogen alone.
In the 6th and oldest study (Studd 1992) in women both with and without hysterectomy, adding implants of testo 75mg 6mthly to Esto 100mg 6mthly made no difference over esto alone, possibly because the of the supraphysiological esto level attained (mean ~1.9nmol/L per Studd 2006) and the followup of only 1year.

In the 7th trial of only 6 months(2005), no improvement was seen in BMD on either esto alone or on Esto + testo- but it used oral HRT; lean mass increased only on the combination- so these women would have been less prone to falls and fractures. .

On the baker’s dozen of natural supplements, we have seen bone density increasing steadily by 1% a year - slightly faster in spine than hip- over 15 years in eg a severely osteoporotic woman with chronic active rheumatoid arthritis on prednisone.

After osteonecrosis the results with hyperbaric oxygen added to the natural supplements appear useful to justify it’s use to salvage whats left ..

HRT AND FRACTURES:

IN the Women’s Health Initiative,

the fracture rate in those with womb was 0.15%pa,
and E+P reduced this by 34% over 5.6yrs;

in those post hysterectomy ie longer without hormones,
the fracture rate was 0.17%pa,
and E alone reduced this by 39% ie 60% still had long bone fractures.

No trials have measured fracture rate on TRT in women;
but we never see women on TRT have spontaneous limb fracture.

Only androgen improves muscle strength;
HRT suppresses relative androgen levels.
so why must women go without replacement androgen?

ndb

Use of platelet-rich plasma in the management of oral biphosphonate-associated osteonecrosis of the jaw: a report of 2 cases. J Oral Implantol. 2007;33:371-82 Lee CY, ea
Bisphosphonates (BP) are nonhormonal medications used in the treatment of various bone malignancies and metabolic conditions. Since 2003, there have appeared a significant and growing number of articles in the worldwide medical and dental literature describing the complication of an osteonecrosis of the jaws associated with the intravenous and, most recently, the oral form of BP medication that has been refractory to any definitive form of treatment. The authors have successfully managed 2 patients taking the oral form of BP with adjunctive treatment using platelet-rich plasma (PRP), and in one case with hyperbaric oxygen (HBO). We were able to obtain complete remission in each case, which is defined as resolution of pain and complete closure of exposed bone in the jaws. The purpose of this report is to describe a treatment protocol and the rationale for using PRP and HBO to obtain complete remission of this new pathologic condition.

Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series.J Oral Maxillofac Surg. 2007 Jul;65(7):1275-6. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, Kraft KH, Boneta O, Moon RE, Piantadosi CA.Duke University Medical Center, Divers Alert Network, Durham,.
PURPOSE: Bisphosphonate (BP)-associated osteonecrosis of the jaw (ONJ) is an emerging problem with few therapeutic options. Our pilot study of BP-ONJ investigated a possible role for hyperbaric oxygen (HBO(2)) therapy. PATIENTS AND METHODS: A total of 16 patients, ranging in age from 43 to 78 years, with BP-ONJ were treated with adjunctive HBO(2) between July 2003 and April 2006. Staging was based on the size and number of oral lesions. Clinical response after treatment and at distant follow-up; the odds of remission, stabilization, or relapse; and time to failure analysis were calculated. RESULTS: The median time on BP therapy before appearance of ONJ symptoms was 18 months, and that from symptom onset to HBO(2) therapy was 12 months. Fourteen of 16 patients (87.5%) improved in stage. The size and number of ONJ lesions were decreased after HBO(2) therapy (P < .001 and P = .008, respectively; Wilcoxon signed-rank test). Immediately after HBO(2) therapy, 7 of 16 patients (44%) were in remission and 8 (50%) had stabilized; however, stabilization without remission was sustained in only 2 patients. At follow-up, 10 of the patients (62.5%) were still in remission or had stabilized. The 7 patients who continued on BP treatment during HBO(2) therapy had a shorter time to failure (8.5 months; 95% confidence interval [CI] = 7.1 to 9. than those who discontinued the drug (20.1 months; 95% CI = 17.5 to 23.9; P = .006 by the log-rank test). Clinical response was not associated with cancer type or malignancy remission status. CONCLUSIONS: Adjunctive HBO(2) therapy may benefit patients with BP-ONJ; however, the outcome is improved with cessation of BP administration.

3: Am J Otolaryngol. 2007 May-Jun;28(3):158-63.
Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases