Reported by: Dr. V.S. Karra, Ph.D.
The European equivalent of the US Food and Drug Administration (FDA) yesterday recommended withdrawing calcitonin nasal spray — indicated for treating osteoporosis in the European Union — because of an increased risk for cancer.
The European Medicines Agency (EMA) also said that the long-term use of calcitonin-containing medicines delivered by injection or infusion increases the risk for cancer. Calcitonin in any formulation should not be used to treat osteoporosis at all, the agency said.
In the United States, 2 nasal-spray versions of calcitonin are FDA-approved for treating postmenopausal osteoporosis in women: Fortical (Upsher-Smith Laboratories) and Miacalcin (Novartis). Neither of the labels for the 2 drugs contains restrictions on how they should be used or a warning about the risk for cancer.
Calcitonin, also called calcitonin-salmon, is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon.
The EMA said it based its recommendations on a review of the benefits and risks of calcitonin-containing medicines. Conducted by the agency’s Committee for Medicinal Products for Human Use (CHMP), the review encompassed available data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources.
CHMP found that “a higher proportion of patients treated with calcitonin for long periods of time develop cancer of various types, compared with patients taking placebo.” The increase in cancer rates ranged from 0.7% for oral formulations to 2.4% for the nasal formulation. CHMP concluded that the benefits of calcitonin for osteoporosis did not exceed the risks. The nasal spray’s only indication is for osteoporosis, thus justifying the drug’s removal from the market.
As a solution for injection or infusion, calcitonin should be administered for no more than 4 weeks to prevent acute bone loss resulting from sudden immobilization, and normally for no more than 3 months to treat Paget’s disease, the EMA said. The agency did not specify a time frame for the short-term use of calcitonin for treating hypercalcemia caused by cancer.
For further details go to their website
Dr. Karra,
Thank you for this post. Alerts on needs for drug withdrawals are definitely– providers of informational insights into the course of unexplainable onset of symptoms or new diagnosis.
The novel drug, a nasal administered calcitonin poses an interesting problem. It lowers serum calcium, or in any case is expected to suppress bone mineral loss in postmenopausal osteopenia. The risk of using the drug may be unknown in the long run, but the putative equal risk of cancer is not a valid weight against it because cancers and their natural behaviors are very organ specific. The cost of fracture related falls in the elderly is a problem with sarcopenia and osteopenia at its base.
The review of this new approach to something that could have widespread use warrants an understanding of bone growth, remodeling, and disease. The development of long bones is by metaphyseal osteonal development from a cartilaginous growth plate, and in width by periosteal growth. The growth of bone is carried out by removal by osteoclasts with refill by osteoblasts. It takes 150 osteoblasts to refill an amount of matrix removed by 1 osteoclast (1 micron per day). This was established by the very tedious measurements of the late Lent C Johnson, at the Armed Forces Institute of Pathology Orthopedic Branch before the use of radioactive tracers, although he did measure fluxes using tetracycline.
The Armed Forces Medical Museum, more astounding than the Hunter Museum in Glasgow, was a national treasure closed despite the efforts of the late Senator Ted Kennedy.
The growth of bone at the metaphysic is interrupted by hypovitaminosis C and D. Vitamin C, extracted from paprika by Szent-Gyorgyi, is essential for cross-linking collagen in the matrix. A deficiency in childhood results in Scurvy, and is related to the use of lime on long voyages. A deficiency of vitamin D results in Rickets in children and Osteomalacia in adults. The poor matrix formed can’t be removed by osteoclasts to form new bone. Osteomalacia is important in patients with chronic renal failure on dialysis. The vitamin D story is of a hormone, and it is converted to 25-hydroxy by the kidney, and either to 1,25 (active) or 24,25 (inactive) dihydroxycholecalciferol by the liver, promoting calcium uptake by calcium binding protein in the small intestine.
The skeleton remodels throughout life. The remodeling is dependent of muscle tension. The ratio of muscle to bone is 4:1. When there is sustained inactivity, there is sarcopenia and bone loss follows. Homeostasis is maintained by the osteocyte. It has to be stressed that exercise is necessary throughout life. Metabolic bone disease in the sense of hypercalcemia and regulation of bone remodeling is disordered in hyperparathyroidism with the genesis of osteitis fibrosa cystica, usually seen as cystic lesions on the ribs. This is characterized by waves of osteoclasts removal of bone. The hyperplasic parathyroid glands are easily identified at surgery. The most remarkable disorder is Paget’s Disease, a disordered removal of bone resulting in “pumice bone”, which fractures.
The question is where calcitonin fits into the process.
Dr. Larry,
Thank you for the excellent review of all the corollary of issues involved in the pathophysiology of bone disease and osteopenia for which the Calcitonin is indicated.
I believe that the recent discovery that Calcium supplements cause calcification and sediments in the body vasculature, thus lowering the amount of daily mg of Calcium supplementation – if combined with potential decline of prescribed Calcitonin — may on the long run be manifested in an increase of preventable Falls.
I hadn’t read that. Dietary calcium is easily absorbed, and seafood is, of course rich in calcium. Many of the supplements taken have both calcium and vitamin D3, and some also have Mg. It turns out that the reference range used for serum magnesium is not useful because mg is intracellular, so that it is not a measure of hypomagnesemia, which hasn’t received much attention.
Getting back to your point, the calcification of peripheral vessels could well be related to oxidative stress and tied to endovascular NO synthase. The increase in falls that you refer to might be related to the calcification in arteries that can be seen on x-ray, which could coexist with chondromalacia /osteoarthritis, muscle loss, dystrophic calcification (conjecture) with age and inactivity. A paper that is not yet published indicates that an increased pro-oxidant-antioxidant balance test in thrombo-angiitis obliterans is indicative of impairment of the oxidative and anti-oxidative pathways.
But then we have many aging patients with CHF taking either b-type or the pro b-type amino terminal natriuretic peptide. The BNP is mostly eliminated by the vascular endothelium. I don’t know what that means. The recent caution about TDZs because of muscle pain, perhaps needs further attention with respect to oxidative and anti-oxidative pathways.
Dr. Larry,
All points are valid. Like your new awareness to eNOS, fast study here, a virtue that we both share,
Aviva
You have raised very important points.
First thing is first (while accepting the fact that biology is more complicated than what we believe that we know),
Maintaining blood calcium concentrations within a tight normal range is critical and any deviations, above or below the normal range, frequently lead to serious disease. Low blood calcium concentration in blood lead to condition called “Hypocalcemia ” where this disorder causes increased neuromuscular excitability and include muscle spasms, tetany and cardiac dysfunction, whereas “hypercalcemia” (concentration of calcium higher than normal range in blood) can lead to diffuse precipitation of calcium phosphate in tissues, leading to widespread organ dysfuncion and damage. Thus it is critical to maintain the normal concentration of calcium and phosphate in blood (homeostasis) and extracellular fluid at saturation point. Such regulatory function is largely the duty of ‘robust endocrine control systems’.
Now, calcium is majorly located at bone, intracellular and, extracellular fluid and blood. To maintain the homeostasis in blood and thereby in others majorly regulated by three organs – small intestines, bone and kidney. The kidney plays a critcal role in such homeostasis, i.e., under normal blood calcium concentrations, almost all of the calcium that enters glomerular filtrate is reabsorbed from the tubular system back into blood, which preserves blood calcium levels. If tubular reabsorption of calcium decreases, calcium is lost by excretion into urine. This function of kidneys is managed through the concerted action of hormones (especially parathyroid).
e.g.,
Parathyroid hormone serves to increase blood concentrations of calcium by Stimulating production of the biologically-active form of vitamin D within the kidney. The most important effect of vitamin D is to facilitate absorption of calcium from the small intestine and also, just like parathyroid hormone, Vitamin D enhances fluxes of calcium out of bone. This clearly demonstrates the critical regulatory role of parathyroid hormone.
On the contrary ‘Calcitonin’ is secreted in response to hypercalcemia (calcium levels above normal range) to minimize fluxes of calcium from bone into blood while enhancing excrection of calcium into urine by suppressing the renal tubular reabsorption of calcium thereby reducing blood concentrations of calcium, i.e., maintining saturation point.
Calcitonin is a hormone that functions to reduce blood calcium levels. The major source of calcitonin in mammals is from thyroid gland but it is also synthesized in a wide variety of other tissues, including the lung and intestinal tract.
To sum up:
what happens during hypocalcemia (calcium below normal range) is that parathyroid gland increases the production of parathyroid hormone which inturn increases Vitamin D (to pump calcium from intestines into blood to maintain homeostasis). Since the function of calcitonin is to eliminate calcium from the system thru urine by controlling the tubular functions in kidney, here in hypocalcemia the secretion of calcitonin is minimized.
And exactly the revers happens in case of hypercalcemia, i.e.,, lowered secretion of parathyroid hormone and therefore vitamin D, while increasing the secretion of calcitonin to eliminate calcium from the system thru urine (while minimizing fluxes of calcium from bone into blood). This probably explains why ‘Calcitonin therapy’ is recommended in hypercalcemic condition in Cancer patients – to excrete calcium from the system thru urine.
Having said that it is important to remember that “although calcitonin has significant calcium-lowering effects in some species, it appears to have a minimal influence on blood calcium levels in humans.”
Now, for a second lets go back to Osteoporosis – just an example. Osteoporosis is a bone disease that leads to an increased risk of fractures which is primarily due to decreased bone mass (probably not due to changes in conc, of ions and parathyroid hormone). This is one of the conditions in which Calcitonin is prescribed (as a nasal spray).
CHMP noted that a higher proportion of patients treated with calcitonin for long periods of time develop cancer of various types, compared with patients taking placebo.
Also noted that the increase in cancer rates seen with calcitonin varied between 0.7% in studies with the oral formulation to 2.4% in the studies with the nasal formulation.
{Here there seem to be an ‘enough’ room for improvement in changing the strategy to sustain the calcitonin market as far as the industry is concerned while minimizing the risk factors for the patients who may be in desperate need of this treatment}
Taking into account these and other factors CHMP concluded that the benefits of calcitonin did not outweigh the risks in ‘this’ condition.
As the nasal spray is only (2.4% of chances of getting cancer) used in osteoporosis, the CHMP recommended that this formulation should no longer be used.
The benefit-risk balance remains positive only for the following uses:
Treatment of Paget’s disease for patients who cannot be treated with alternative treatments,
Prevention of acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures, and
Treatment of hypercalcaemia caused by cancer.
However, the CHMP recommended that even for these uses calcitonin treatment should be given for the shortest possible time using the smallest effective dose.
Ref: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Calcitonin_31/WC500130149.pdf
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Calcitonin/human_referral_000319.jsp&mid=WC0b01ac0580024e99
Recent development in improving the condition of osteoporosis is note worthy:
(http://tginnovations.wordpress.com/2012/07/23/silica-nano-particles-as-a-pharmacological-agent-to-enhance-bone-mineral-density-and-protect-against-bone-fracture-bioactive-silica-based-nanoparticles-stimulate-bone-forming-osteoblasts-suppress-bo/)
Dr. Karra, thank you for your thorough reply clarifying the mechanism of action and the three conditions of exclusion to the proposed suggestion of nasal calcitonin withdrawal from market use.
Where is the data that demonstrates the causality of cancer by nasal calcitonin? How many patients does 2.4% represent? I have serious concerns about the legitimacy of this study for two reasons:
1. the vehemence of the CHMP in recommending removal of calcitonin from the market. Is a 2.4% increase statistically significant? It’s not like “If you take this product, you have a significant risk of developing cancer.” There has been no proof that X causes Y.
2. As stated on the EMA website: (accessed 7/24/2012): http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Calcitonin/human_referral_000319.jsp&mid=WC0b01ac0580024e99
“Why were calcitonin-containing medicines reviewed?
This review was initiated following preliminary findings from two studies of an unlicensed oral calcitonin medicine, which pointed to a possible association with prostate cancer.”
It seems rather odd to pull a medicine that is indicated to treat post-menopausal osteoporosis due to a miniscule increased risk of prostate cancer. The last time I checked patients who are post-menopausal are not susceptible to prostate cancer because THEY DON’T HAVE A PROSTATE!
I think the EMA should take a very long look at the data before rushing to judgment on a product that has been used by physicians for nearly 30 years.
Mr. White, Hello
Thank you for all the points very well taken in your comment above.
Drug removal from the market requires cross validation and replication. Indeed prostate cancer and osteoporosis in the aged female are orthogonal.
I requested two of my team members to reply to you.
May I invite you to Join our Scientific website as GUEST author. Please review other posts, including my own.
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Hello,
all the points are well taken and as it is obvious it does not look like an alarming situation. The %s are insignificant and types of cancers and gender is not obvious. Taking into account the available data on their website it is not clear about the points raised and discussed elsewhere except the ‘nasal spray’ usage and that to its 2.4% is insignificant (unless it is explicitly presented).
To me it appears that EMA’s primary concern is about ‘nasal spray’ that seems to have caused 2.4% rise in cancer risk………… and at the same time type of cancer is not mentioned, except prostate which is as Dr. Aviva and you pointed out “orthogonal”. Unless we have access to what kind of cancer it is in long term usage based on gender would be more useful to draw any definite conclusions. If there is any evidence of uterine/ovarian/Skene’s gland(a female prostate), (a substitute to prostate) cancer then the dynamics would be different.
As far I can recall, in mentioned condition – osteoporosis – postmenopausal (type 1) is more common in women and type-2 or senile osteoporosis occurs after age of 75 and is seen in both females and males at a ratio of 2:1. Finally, secondary osteoporosis may arise at any age and affect men and women equally.
I think what we can take from the conducted study and recommendations made by EMA is:
1. certainly more controlled analysis need to be conducted before taking any definite conclusions.
2. Taking into account the safety of our patients one can reconsider nasal spray re-formulation possibility or shifting to oral formulation where % effected is much less significant?
3. in other disease conditions EMA has asked for modified data insertion into the leaf left to control the treatment practices as part of a preventive measure.
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/07/WC500130148.pdf
Dr. Larry,
Thank you for your contributions to the discussion, above. I agree with the CARDINALITY of meta-analyses in the 21st century “evidence-based medicine”. This is the ONLY way to go — it is a difficult way, though since each of the studies included in the meta analysis was design with a different research goal in mind. This is not the case regarding multi site clinical trials data analysis.
The endgame here may be zero, Very well put !!
Dr. Karra,
Thank you for your comprehensive reply to the concerns raised by Mr. White. I agree with all the points made.
I can’t improve on the comments of Dr. Karra and Dr. Lev-Ari. It is odd that the use of the drug went without notice of severe adverse effects for 30 years, which is a long time. So then one has to ask what is changed except the mode of intake.
There is no doubt that the reference to 2.4% change has no relationship to cause and effect, and it lights up the tyranny of P (p < 0.05).
It was a review of meta-analyses that led the Chief of Cardiology at Cleveland Clinic to challenge the use of Avandia. I think that "evidence-based medicine" will have to become more focused on large, complete data sets that can be combined into one. Then we shall have a better and safer conclusion.
We are closer to that now than we have ever been.
With respect to Paget's disease, and to hypercalcemia from metastatic disease, I'm afraid that short term use has no meaning, and I have reservations about real effectiveness. The rate of destructive bone loss exceeds the physiological ability to refill lost bone, and the new bone would take years to remodel to the same quality as that which is lost.
That is a separate issue than what has been raised about adverse risk. The endgame here may be zero.
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