This column last considered bisphosphonates BPN in February. This reviews some new papers published since.
ADVANCED CANCER with bone spread: Recent major (Cochrane) reviews confirm that BPNs may be valuable in advanced prostate and breast cancer , for reducing skeletal events and maybe pain, although they do not clearly influence disease progression or patient survival.
OSTEOPOROSIS: It is now almost 5 years since the balloon went up on the unnecessary major risks of BPN for osteoporosis. So anyone who was prescribed these dangerous drugs since then for osteoporosis, without the rare special indications, and who develops BNP-related complications (or osteoporosis-related fractures) has a strong case for heavy damages against the prescriber, the dispensing pharmacy and regulator eg the State clinic or medical plan who/which advised/ allowed use of the drug for that condition. .
Bisphosphonates were invented over a century ago but developed over the last 40years for clinical treatment of metabolic bone diseases, with the first human trials reported about 35 years ago (Heaney 1976). Why have they been exhaustively tested and now routinely used for prevention and treatment of aging osteoporosis, despite their considerable cost especially risks, and lack of global benefit?
Obviously because as patented designer drugs they are profitable to the Disease Industry – despite the fact that their biggest section on Wiki is about their rare but major adverse effects- to quote Wiki :
- Oral BPN can cause upset stomach, inflammation and erosions of the esophagus,
- Intravenous BPN can give fever and flu-like symptoms after the first infusion. The slightly increased risk for electrolyte disturbances is not enough to warrant regular monitoring.
- BPN have been associated with osteonecrosis of the jaw – the mandible twice as frequently affected as the maxilla- and most cases occurring following high-dose intravenous administration for cancer patients. Some 60% of cases are preceded by a dental surgical procedure (that involve the bone).
- severe bone, joint, or musculoskeletal pain has been reported.
- BPN use ( zoledronate and alendronate) is a risk factor for atrial fibrillation in women. The inflammatory response to BPN or fluctuations in calcium blood levels have been suggested as possible mechanisms..
- Matrix metalloproteinase 2 may be a candidate gene for BPN-associated ONJ since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side effects of BPN.
- Long-term BPN use resulting in severe or over suppression of bone turnover especially at the femur sub-trochanteric region. Micro-cracks in the bone maybe unable to heal and eventually unite and propagate, resulting in atypical fractures, which tend to heal poorly and often require some form of bone stimulation eg bone grafting.
NO COMPELLING INDICATIONS FOR BPN IN OSTEOPOROSIS: the Wiki entries for BPN and osteoporosis are cleverly written by BPN promoters / marketeers – they fails to justify why BPNs are “the most popular first-line drug”… and the overwhelming evidence that favours combined natural supplements: eg that in the Womens Health Initiative, appropriate hormone replacement HRT ie started soon after menopause is safe up to 10 years of use, halved fracture rate and colon cancer, and lowered all other chronic major degenerative diseases AND breast cancer AND premature deaths by a third. BPNs have risks but no benefits other than fracture reduction- ie for osteoporosis, no compelling indications and the legal eagles are hungry.. .
BPN-ASSOCIATED OSTEONECROSIS IN LONG BONES: Guanabens from Spain first described long bone fractures related to BPN in 1994, and more such cases (iatrogenic Toulouse-Lautrec disease) are reported now from the UK.
ATRIAL FIBRILLATION: Denmark reports some 30% increase in potentially crippling atrial fibrillation in patients with fractures treated with BPN – whereas it is common cause that appropriate supplements drastically reduce arrhythmia eg fish oil halves sudden death.
Italy now reports increase in hypocalcemia and raised serum creatinine ie kidney impairment after BPN for cancer . . Sweden reports no benefit of 2 years’ BPN on knee prosthesis migration. The incidence of metabolic bone disease and all other system complications in intensive care is notorious – and a Princeton report gives no justification for BPN use in ICU when all the safe natural supplements are essential and ensure better protection globally..
A Canadian study shows that ” managed intervention” after osteoporotic hip fracture prevented 4 new hip fractures and gained 4 quality life-years – but the available abstract omits what the interventions were, and whether survival was increased.
And while all rational evidence-based appropriate prevention and treatment of osteoporosis – the permanent baker’s dozen of safe natural supplements- reduce all-cause chronic degenerative disease and mortality by at least a third, without any risks, – BPNs have increasingly recorded risks both short term and long term, with no extraskeletal benefits, despite reducing the fracture risk (spine -Cummings 2002; hip Nguyen 2006) by up to a half.
OSTEONECROSIS OF THE JAW ONJ: first reported in 2003, only 26 cases of ONJ on oral BPN could be found reported worldwide up to Sept 2006 in a 2007 University Pennsylvania study . Only 15 % were men, and the majority involved the mandible. Now Israel alone reports another 100 cases of BNP- related jaw osteonecrosis – fossy jaw – and 16% were on oral BPN. The incidence of OJN is speculated to be between 5% and 11% in cancer patients treated with BPN.
A world-wide panel produced the 2008 Canadian Consensus Practice Guidelines for BNP Associated Osteonecrosis of the Jaw, but did not estimate the incidence of ONJ. It concludes that “High-dose intravenous BNP have been identified as a risk factor for ONJ in the oncology patient population. Low-dose BNP use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of ONJ” “BPNs have become a cornerstone in the management of skeletal complications of malignancy as well as osteoporosis and metabolic bone disease, as these agents offer tremendous benefit to those with malignancy or metabolic bone disease” Due to limited and misleading public information regarding ONJ, many patients have discontinued BPN treatment, resulting in inadequate care of the underlying skeletal condition.”
But the Canadian Consensus paper fails to clarify in what way BPN offers “tremendous benefit” to those with osteoporosis? The consensus of the majority of practitioners who do not recommend BPN for osteoporosis is that evidence still shows that appropriate HRT with other standard supplements is the best prevention and treatment not just of osteoporosis but of all the common major degenerative diseases of aging. (The International Menopause Society). This eternal truth and aim- the wellbeing of seniors- is the imperative, not the wishful thinking of Big Pharma to replace natural supplements with designer magic bullets for each disease.
By far the most comprehensive and objective review is the American Association of Oral and Maxillofacial Surgeons Position Paper January 2009 Update on Bisphosphonate-Related Osteonecrosis of the Jaw BRONJ: Indications and benefits of BPN therapy:
Intravenous (IV) BPN are primarily used and effective in treatment and management of cancer-related conditions including hypercalcemia of malignancy, bone metastases such as breast, prostate and lung cancer, and multiple myeloma- for which the clinical efficacy of IV BPN is well established.
BPN have not been shown to improve cancer-specific survival, but they have had a significant positive effect on the quality of life for patients with advanced cancer involving the skeleton.
Oral BPN: By far the most prevalent and common indication is osteoporosis and osteopenia. They are also used for a variety of less common conditions such as Paget’s disease of bone, and osteogenesis imperfecta of childhood.
INCIDENCE OF BRONJ: Based on case series, case-controlled and cohort studies, estimates of the cumulative incidence of BRONJ range from 0.8%-12%.
ORAL BPN BRONJ: Surveillance data from Australia estimated the incidence of BRONJ for patients treated weekly with alendronate as 0.01-0.04%. In a survey study of over 13, 000 Kaiser-Permanente members, the prevalence of BRONJ in patients receiving long-term oral BPN therapy was reported at 0.06% (1:1,700).
Demographic and systemic factors: In the original Position Paper, age, race, and cancer diagnosis with or without osteoporosis were reported as risk factors for BRONJ. Seven studies report increasing age as consistently associated with BRONJ. Sex was not statistically associated with BRONJ. Other systemic factors or conditions, i.e., renal dialysis, low hemoglobin, obesity, and diabetes, were variably reported to increase the risk for BRONJ. Malignancy type was not statistically associated with an increased risk for BRONJ.
Genetic factors: Sarasquete et al, demonstrated that genetic perturbations, i.e. single nucleotide polymorphisms (SNPs), in the cytochrome P450-2C gene (CYP2C8) gene were associated with an increased risk for BRONJ among multiple myeloma patients treated with IV BPN.
Preventative factors The AAOMS Taskforce on BRONJ recommended that patients undergo dental evaluations and receive necessary treatment prior to initiating IV BPN therapy. In addition, given the long-term biologic activity of IV BPN one may hypothesize that different dosing regimens may be equally effective and decrease the risk for BRONJ.
Using a retrospective cohort study design, Coso et al, evaluated the BRONJ and skeletal-related events e.g. pathologic fracture in multiple myeloma patients using different dosing schedules for zoledronate. These findings suggest that alternative dosing schedules that reduce IV BPN exposure have comparable outcomes in terms of preventing SREs and a decreased risk of BRONJ.
The effectiveness of hyperbaric oxygen therapy as an adjunct to non-surgical and surgical treatment is under investigation at two institutions where a randomized controlled trial is underway. Preliminary results have shown some improvement in wound healing and long-term pain scores, but its use as the sole treatment modality for BRONJ cannot be supported at this time.
Yet despite the fact that osteoporosis and fractures are closely related to and occur along with the major causes of aging disability and premature death – 20% of osteoporotic hip fracture victims die within a year- BPNs have not been shown to reduce any let alone all the other aging diseases let alone premature deaths. The closest a study came to assess the issue was a Singapore analysis of the 30year old clodronate used for up to 2-3 years after breast cancer – which drug showed no influence on overall survival.
This failure of global benefit of BPNs – which are in fact never indicated except rarely eg as palliation in preterminal cancer bone lesions – raises the question of criminal negligence when doctors prescribe and medical schemes and Regulators allow BPN use for osteoporosis. Why are BPNs allowed and prescribed when they have no global benefit but numerous serious risks; and when conventional lowcost natural supplements combined do nothing but global good. eg essential fish oil, essential vigorous-dose blend of vitamins-minerals-biologicals-herbs, essential appropriate HRT , and essential galega-metformin in the overweight let alone obese each lower all-cause chronic morbidity and death by a third to a half.
It is no defence that adverse effects are rare when they are sometimes deadly, and never worth the risk of these drugs since there is rarely overwhelming need to prescribe such drugs- for which there are safe natural and far more effective alternatives.
CASE REPORTS: In 2007 we saw a well-built physically active woman of 61years, whose bone density had fallen some 9% on regular DEXA screening since menopause despite the usual calcium-vitamin D supplement. In 2008 she decided to delay HRT because of strong family history of breast cancer. A year later at followup DEXA on just fish oil plus a modest dose of the standard HealthSpan For-Bone supplement blend (calmag zinc boron manganese; proline; and vits B6-9-12 – C- D3 & K2), her DXA BMD has risen 2% (2.5% at the spine, 1.5% at the hip).
A small slim 61year old bookkeeper presented a year ago on just calcium & vitamin D, her 2007 DEXA spinal density 0.99 having fallen 1% from 2005 ie T -1.6 but her hip down 6.3% from 0.792 to 0.764 ie T-2. Since then, on the Bone Blend and a little estrogen-progesterone-testosterone cream daily, her spine has stayed constant but her hip BMD has risen 2.4% to 0.783.
A new review from Toulouse France has the last word: “Postmenopausal osteoporosis is a chronic disease which justifies long-term treatment. Efficacious available modern fracture-reducing drugs raise the question of the best treatment strategy in postmenopausal women . In this regard, HRT, which allows a more global approach to the menopause-induced consequences of hormone deficiency than the sole prevention of osteoporosis, should be privileged… Use of BPN or strontium ranelate should be thus (at best) be reserved for a more advanced age, when the prevention of hip fracture becomes mandatory“. .
Yet, because it is profitable, the fashion grows to treat the elderly with grossly expensive designer oral strontium, or designer injections of BNP or hormone analogues (of calcitonin or parathormone) – despite the fact that these experimental agents have no extra-skeletal benefits (ie improving cardiovascular, muscle, immune, brain function), have never been tested in longterm studies for at least 6-10 years to test their safety as has eg HRT in the Nurses’ and WHI studies.
But millions of years of bipedal evolution, and numerous studies over the past century, show that all that is required to maintain maximum mobility, mind and mood to enjoy life is lifelong supplements as listed above, appropriate to youth, parents, the middle-aged and seniors.. including healthy seniors’ sexuality. It is too late postponing prevention till wished-for healthy advanced age- which most do not reach due to early demise, or irreversible crippledom from largely avoidable fractures, strokes, heart failure, arthritis, or dementia.
The Israelis’ maxillofacial team lament that “Solutions for decreasing morbidity and poor outcome of ONJ remain elusive.” The answer is painfully obvious: avoid iatrogenic ONJ by avoiding BPN -even orally- except for advanced cancer with bone metastases, but back up lower dose BPN with all the anabolic supplements.
A risk of “only” 7 in 10 000 may reassure a patient being offered BPN for osteoporosis- but if she decides to sue for damages for prescription of totally unnecessary hazardous therapy, the prescriber doesnt have a leg to stand on when the gold standard is appropriate titrated supplements (including HRT) without risks since they reduce all risk by at least one-third.
As wise Chinese taught 2600 years ago, Society, Authorities, Regulators, health professionals have a sacred obligation to above all else prevent avoidable premature death and crippledom with the freely available and low-cost well-proven natural supplements. These must prevail despite the best efforts of Big Business, Big Pharma and their academic and political lobbyists (Governments, Regulators) worldwide to ignore if not outright suppress safe effective old natural supplements (as the FDA and EU are doing) in favour of Diseases and Modern Drugs that Pay – but do not reduce all-cause disease and mortality .