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Calcium, Bone Health & Fracture Risk

Dean Pomerleau

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Bone health is a concern for CR practitioners, since CR practitioners have been shown to have less bone mass (along with less fat and lean mass) than the general population, both in a one-year randomized control trial [3], and more significantly in a study of a number of us long-term CR practitioners by Luigi Fontana et al. [4]. Fortunately, bone quality does not appear to be compromised in us long-term practitioners [4].


Due to our lower total body mass (hence less force when we fall / crash) but also less fat mass (hence less padding when we fall / crash), it's not clear what the net effect of our thinner but structurally-sound bones is on our risk of fracture.


So it was interesting to see that two new meta-analyses in this month's British Medical Journal by the same group of New Zealand researchers addressed the relationship between dietary and supplemental calcium (with or without vitamin D) on bone mineral density (BMD) [1] and fracture risk [2]. After looking at all the available epidemiological and randomized control trials of the effects of calcium intake on BMD and fracture risk, the authors conclude that:


Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture. [1]



Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent. [2]


While [2] did find supplemental calcium was associated with a small reduction in total and vertebral fractures, there was no reduction in hip or wrist fractures, and some of the included studies were suspect / low quality. When they included only the four most well-conducted randomized control trials in their analysis (which included 44,500 subjects), supplemental calcium didn't reduce total fractures or fractures at any specific site. 


Overall, it doesn't appear that either dietary or supplemental calcium (with or without vitamin D) will improve our odds of avoiding fractures. At the same time bisphosphonates and other BMD boosting medications have a checkered track record and sometimes serious side effects [5].


So interventions like exercise [4], maintaining our coordination & balance via activities like yoga and sports, and minimizing risk of traumatic injuries (e.g. by wearing seat belts when driving, helmets when biking, holding handrails when climbing stairs etc.) appear to be the best strategies for keeping our bones safe. 





[1] BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h4183(Published 29 September 2015)

Cite this as: BMJ 2015;351:h4183
Calcium intake and bone mineral density: systematic review and meta-analysis
Vicky Tai, William Leung, Andrew Grey, Ian R Reid, Mark J Bolland
Objective To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and, if so, whether the effects are similar to those of calcium supplements.
Design Random effects meta-analysis of randomised controlled trials.
Data sources Ovid Medline, Embase, Pubmed, and references from relevant systematic reviews. Initial searches were undertaken in July 2013 and updated in September 2014.
Eligibility criteria for selecting studies Randomised controlled trials of dietary sources of calcium or calcium supplements (with or without vitamin D) in participants aged over 50 with BMD at the lumbar spine, total hip, femoral neck, total body, or forearm as an outcome.
Results We identified 59 eligible randomised controlled trials: 15 studied dietary sources of calcium (n=1533) and 51 studied calcium supplements (n=12 257). Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥1000 versus <1000 mg/day and ≤500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥800 mg/day.
Conclusions Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture.
[2] BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h4580(Published 29 September 2015)
Cite this as: BMJ 2015;351:h4580
Calcium intake and risk of fracture: systematic review
Mark J Bolland, William Leung, Vicky Tai, Sonja Bastin, Greg D Gamble, Andrew Grey, Ian R Reid
Objective To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.
Design Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses.
Data sources Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014.
Eligibility criteria for selecting studies Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50.
Results There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58 573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48 967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56 648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51 775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger’s regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44 505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.
Conclusions Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.


[3] Aging Cell. 2011 Feb;10(1):96-102. doi: 10.1111/j.1474-9726.2010.00643.x. Epub

2010 Nov 15.

Reduced bone mineral density is not associated with significantly reduced bone
quality in men and women practicing long-term calorie restriction with adequate

Villareal DT(1), Kotyk JJ, Armamento-Villareal RC, Kenguva V, Seaman P, Shahar A,
Wald MJ, Kleerekoper M, Fontana L.

Author information:
(1)Division of Geriatrics and Nutritional Science, Washington University School
of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.

Calorie restriction (CR) reduces bone quantity but not bone quality in rodents.
Nothing is known regarding the long-term effects of CR with adequate intake of
vitamin and minerals on bone quantity and quality in middle-aged lean
individuals. In this study, we evaluated body composition, bone mineral density
(BMD), and serum markers of bone turnover and inflammation in 32 volunteers who
had been eating a CR diet (approximately 35% less calories than controls) for an
average of 6.8 ± 5.2 years (mean age 52.7 ± 10.3 years) and 32 age- and
sex-matched sedentary controls eating Western diets (WD). In a subgroup of 10 CR
and 10 WD volunteers, we also measured trabecular bone (TB) microarchitecture of
the distal radius using high-resolution magnetic resonance imaging. We found that
the CR volunteers had significantly lower body mass index than the WD volunteers
(18.9 ± 1.2 vs. 26.5 ± 2.2 kg m(-2) ; P = 0.0001). BMD of the lumbar spine (0.870
± 0.11 vs. 1.138 ± 0.12 g cm(-2) , P = 0.0001) and hip (0.806 ± 0.12 vs. 1.047 ±
0.12 g cm(-2) , P = 0.0001) was also lower in the CR than in the WD group. Serum
C-terminal telopeptide and bone-specific alkaline phosphatase concentration were
similar between groups, while serum C-reactive protein (0.19 ± 0.26 vs. 1.46 ±
1.56 mg L(-1) , P = 0.0001) was lower in the CR group. Trabecular bone
microarchitecture parameters such as the erosion index (0.916 ± 0.087 vs. 0.877 ±
0.088; P = 0.739) and surface-to-curve ratio (10.3 ± 1.4 vs. 12.1 ± 2.1, P =
0.440) were not significantly different between groups. These findings suggest
that markedly reduced BMD is not associated with significantly reduced bone
quality in middle-aged men and women practicing long-term calorie restriction
with adequate nutrition.

PMCID: PMC3607368
PMID: 20969721


[4] Arch Intern Med. 2006 Dec 11-25;166(22):2502-10.

Bone mineral density response to caloric restriction-induced weight loss or
exercise-induced weight loss: a randomized controlled trial.

Villareal DT(1), Fontana L, Weiss EP, Racette SB, Steger-May K, Schechtman KB,
Klein S, Holloszy JO.

Author information:
(1)Division of Geriatrics and Nutritional Sciences, Department of Medicine,
Washington University School of Medicine, St Louis, MO 63110, USA.

Erratum in
Arch Intern Med. 2007 Mar 12;167(5):452.

BACKGROUND: Bone loss often accompanies weight loss induced by caloric
restriction (CR), but whether bone loss accompanies similar weight loss induced
by exercise (EX) is unknown. We tested the hypothesis that EX-induced weight loss
is associated with less bone loss compared with CR-induced weight loss.
METHODS: Forty-eight adults (30 women; 18 men; mean +/- SD age, 57 +/- 3 years;
and mean +/- SD body mass index, 27 +/- 2 kg/m2) were randomized to 1 of 3 groups
for 1 year: CR group (n = 19), regular EX group (n = 19), or a healthy lifestyle
(HL) control group (n = 10). Primary outcome measure was change in hip and spine
bone mineral density (BMD). Secondary outcomes were bone markers and hormones.
RESULTS: Body weight decreased similarly in the CR and EX groups (10.7% +/- 6.3%
[-8.2 +/- 4.8 kg] vs 8.4% +/- 6.3% [-6.7 +/- 5.6 kg]; P = .21), whereas weight
did not change in the HL group (-1.2% +/- 2.5% [-0.9 +/- 2.0 kg]). Compared with
the HL group, the CR group had decreases in BMD at the total hip (-2.2% +/- 3.1%
vs 1.2% +/- 2.1%; P = .02) and intertrochanter (-2.1% +/- 3.4% vs 1.7 +/- 2.8%; P
= .03). The CR group had a decrease in spine BMD (-2.2% +/- 3.3%; P = .009).
Despite weight loss, the EX group did not demonstrate a decrease in BMD at any
site. Body weight changes correlated with BMD changes in the CR (R = 0.61; P =
.007) but not in the EX group. Bone turnover increased in both CR and EX groups.
CONCLUSIONS: CR-induced weight loss, but not EX-induced weight loss, is
associated with reductions in BMD at clinically important sites of fracture.
These data suggest that EX should be an important component of a weight loss
program to offset adverse effects of CR on bone.

PMID: 17159017



[5] Acta Medica (Hradec Kralove). 2012;55(3):111-5.

Bisphosphonate-related osteonecrosis of the jaws. A severe side effect of
bisphosphonate therapy.

Janovská Z(1).

Author information:
(1)Department of Dentistry, Charles University in Prague, Faculty of Medicine and
University Hospital, Hradec Králové, Czech Republic. janovani@centrum.cz

Bisphosphonates (BP) are potent inhibitors of bone resorption used mainly in the
treatment of metastatic bone disease and osteoporosis. By inhibiting bone
resorption, they prevent complications as pathological fracture, pain,
tumor-induced hypercalcemia. Even though patient's benefit of BP therapy is huge,
various side effects may develop. Bisphosphonate-related osteonecrosis of the
jaws (BRONJ) is among the most serious ones. Oncologic patients receiving high
doses of BP intravenously are at high risk of BRONJ development. BPs impair bone
turnover leading to compromised bone healing which may result in the exposure of
necrotic bone in the oral cavity frequently following tooth extraction or trauma
of the oral mucosa. Frank bone exposure may be complicated by secondary infection
leading to osteomyelitis development with various symptoms and radiological
findings. In the management of BRONJ, conservative therapy aiming to reduce the
symptoms plays the main role. In patients with extensive bone involvement
resective surgery may lead to complete recovery, provided that the procedure is
correctly indicated. Since the treatment of BRONJ is difficult, prevention is the
main goal. Therefore in high risk patients dental preventive measures should be
taken prior to bisphosphonate administration. This requires adequate
communication between the prescribing physician, the patient and the dentist.

PMID: 23297518

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[Disclaimer: I'm a vegan  :) ]


Hold the presses. One more thing to mention...


The vast majority of studies included in the two meta-analyses discussed in my first post involve getting calcium from supplements or traditional food sources, which almost invariable means dairy products. And as we saw, neither of these seem to improve bone density or fracture risk.


But this (admittedly small) study of postmenopausal Japanese women found that plant sources of dietary calcium, but not animal sources, improved bone mineral density.


So (perhaps) eating more calcium-rich plants, rather than meat and dairy, to get our calcium can also protect our bones.





[1] Nutr Res. 2011 Jan;31(1):27-32. doi: 10.1016/j.nutres.2010.12.005.

Calcium from plant sources is beneficial to lowering the risk of osteoporosis in
postmenopausal Korean women.

Park HM(1), Heo J, Park Y.

Author information:
(1)Department of Obstetrics and Gynecology, Yong San Medical Center, College of
Medicine, Chung Ang University, Seoul, Korea.

Osteoporosis, which has become a serious public health concern, is influenced by
diet, especially calcium intake. Dairy products are a good source of calcium, but
plant calcium may also be important in populations that do not consume a large
amount of milk. The purpose of the present study was to examine the hypothesis
that calcium from vegetable sources is associated with osteoporosis risk and bone
mineral density in postmenopausal Korean women with osteoporosis and age-matched
controls (N = 144). The results of multivariate-adjusted regression analyses
indicated that the intake of calcium, plant calcium, potassium, vitamin A,
carotene, vitamin B(1), niacin, vitamin E, vitamin C, and vegetables was
associated with significantly reduced risk of osteoporosis after adjusting for
age, body mass index, hormone replacement therapy, and energy intake. In
addition, intake of vegetables alone, as well as calcium, plant calcium,
potassium, and antioxidant vitamins (vitamin C, vitamin E, β-carotene), which are
abundant in vegetables, was significantly and positively associated with bone
mineral density. However, in this population of low-dairy consumers, intake of
calcium from meat and dairy products was not related to risk of osteoporosis and
bone mineral density. Our results suggest that high dietary intake of calcium,
especially plant calcium, reduces the risk of osteoporosis and increased bone
mineral density in postmenopausal Korean women. Vegetables may be an important
source of calcium and may also provide vitamins and minerals that exert
additional beneficial effects on the bone.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21310303

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  • 8 months later...

Calcium - Not So Much


This new study [1] came across my radar today in an email from the Physicians Committee for Responsible Medicine:


High Calcium Intake Does Not Protect From Bone Fracture
A high intake of calcium may not offer more protection from bone fractures, according to a study published online in the Journal of Bone and Mineral Research. Researchers measured calcium intake and the number of bone fractures in 6,210 participants who consume plant-based diets from the China Health and Nutrition Survey. Calcium intakes ranging from 275-780 mg/d and 250-650 mg/d for men and women, respectively, were found to be the most protective, with no added benefits for consuming above that range. The authors conclude that a plant-based diet may be associated with lower requirements for calcium intake for bone health, compared with Westernized diets, and suggest that dietary policies reflect this in countries where most of the population's diet is lower in animal products.
Unfortunately the full text is not (yet?) available, so I can't check into the details. But from the abstract below, it looks like there was a pretty dramatic U-shaped curve relating calcium intake and fracture risk among people (esp. men) eating a plant-based diet. The risk of fracture for men in the lowest and highest tertiles were 1.91x and 2.68x higher that the fracture risk of men in the middle tertile. Further:
In non-linear regressions, an increased risk of fracture was associated with dietary calcium intake more than 778 mg/d (multivariable adjusted hazard ratio 2.10, 95% confidence interval [CI] 1.00-4.41) or lower than 275 mg/d (1.74, 95% CI 1.00-3.01) for men...
This seems like more evidence that a moderate amount of calcium is sufficient, and perhaps optimal, for avoiding fractures, at least in folks from the general population eating a mostly plant-based diet.
[1] J Bone Miner Res. Published online May 21, 2016. DOI: 10.1002/jbmr.2874
Long-term low intake of dietary calcium and fracture risk in older adults with plant-based diet: a longitudinal study from the China Health and Nutrition Survey. 
Fang A, Li K, Guo M, He J, Li H, Shen X, Song J.
The aim of this longitudinal study was to investigate long-term associations between low dietary calcium intake and fracture risk in older adults with plant-based diet.Data of self-reported first fracture events of any type from 6210 Chinese men and women, aged 50 years or over and free from fracture at baseline, in a subcohort based on the China Health and Nutrition Survey, were analyzed. Diet was repeatedly assessed by a combination of three consecutive 24-hour individual dietary recalls, and a weighing and measuring household food inventory in each round. The older men and women habitually ingested mean (SD) of 415(147)mg/d and 373(140) mg/d of calcium from plant-based diet, respectively. During a median follow-up of 7.0 years, 127 men (4.34%) and 232 women (7.06% experienced first fracture events.The crude rates were 4.88, 2.55, and 6.83 per 1000 person years at risk for men,and 6.72, 7.10, and 11.0 per 1000 person years at risk for women in the lowest, third, and highest quintile of dietary calcium intake. In non-linear regressions, an increased risk of fracture was associated with dietary calcium intake more than 778 mg/d (multivariable adjusted hazard ratio 2.10, 95% confidence interval [CI] 1.00-4.41) or lower than 275 mg/d(1.74, 95% CI 1.00-3.01)for men,and more than 651 mg/d for women (1.54, 95% CI 1.00-2.38);And a non-significant trend of increase in fracture risk was found below 248 mg/d (1.00, 95% CI 0.67-1.50) in women using restricted cubic spline Cox regression.A relatively low fracture risk is observed in men with dietary calcium intakes of 275-780mg/d and in women with intakes of 250-650mg/d, and higher intakes may have no further benefit for fracture prevention. The patterns of dietary calcium with fracture risk are U-shaped in men and possibly in women.


dietary calcium;plant-based diet;fracture prevention;epidemiological study;China Health and Nutrition Survey
PMID: 27208802
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Hi Dean!


One thing that should be mentioned is osteoporosis.  CRONnies have a tendency towards osteoporosis, as measured by Dexa.


Some years ago, my dexa showed fairly severe osteoporosis (this may in part have been the result of limiting my Vitamin D intake -- in the past, the USDA cautioned against supplementing over some figure that is today considered much too low -- especially in sun-poor Rochester, NY -- but my osteo was probably worsened by CRON).  [i should note that Michael Rae, in a recent post to a newbie, noted that CR people have soft nails -- mine fit that description, as well -- however, nail hardness is a direct correlator to bone strength -- whatever Luigi found.]  


I went on Forteo -- the only medication available that builds bone.  It improved my bone density (as measured by Dexa) for about 8 years (longer than recommended by the FDA) -- and had considerable improvement in my bone density (as measured by Dexa). However, after the ca. 8 years, Dexa showed no further improvement.  So, following the recommendation of my Endocrinologist, and of Prof. Whitfield, of the Canadian CRC in Ottawa (one of the world's foremost experts on osteoporosis), I switched to Prolia (one injection every 6 months).  (Prolia works by interfering with the Rank/Rankl binding -- the result is that some immature osteoclasts do not mature into functioning osteoclasts [which break down bone].)


After 3 years on Prolia, consisent with the recommendations of Prof. Whitfield, and with the consent of my Endocrinologist, I returned (recently) to daily injections of Forteo.  The result is impressive: within a few days, nails changed from soft to hard and strong; and nails are now growing much faster (I have to cut them more often).  I don't qualify for another dexa for about a year -- but I expect that it will continue to show improvement.


I mention this, as I caution CRONnies to not be over-confident in Luigi's small study on some of us -- Michael's correct observation that CRONnies have soft nails (which certainly is true for me, when I'm off Forteo), should, IMO, be a wakeup call -- we're all in danger of osteoporosis, and should be cautious as Dean suggests -- and,IMO, get a Dexa, and, if Dexa shows that you have osteoporosis, try to get your Endocrinologist or Orthopaedist (or Rheumotologist) to prescribe Forteo.


  --  Saul

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I'm glad your osteoporosis seems to be improving. I'm not sure how diagnostic it is, but I've never had weak fingernails, even when practicing a more traditional form of CR. But based on DEXA scans, my bones haven't been that affected - modest osteopenia only. 


Unlike bisphosphonates like Fosamax, which appear to raise the risk of a rare form of jawbone cancer [1], Forteo (teriparatide) appears not to raise cancer risk in humans [2][3], despite appearing to increase the rate of bone cancer in rats [4]. So that's good to hear it's an option if necessary.


But I don't think any of us relish the hassle and discomfort of having to give ourselves daily injections of Forteo, or risk the non-cancer side effects, which reportedly may include:


Serious side effects:

  • feeling light-headed or fainting every time you inject this medicine;
  • fast or pounding heartbeats every time you inject this medicine; or
  • nausea, vomiting, constipation, and muscle weakness.

Less serious side effects:

  • mild dizziness;
  • pain, redness, bruising, itching, or swelling where the medicine was injected;
  • leg cramps;
  • joint pain;
  • cough, sore throat, runny nose;
  • headache or neck pain; or
  • nausea, constipation, diarrhea.

Instead I'm hoping that a good diet, including a modest amount of plant-derived calcium, lots of vitamin D from sun and supplements, along with supplemental strontium and vitamin K2 (from natto), coupled with plenty of weight-bearing exercise, cold exposure and whole body vibration therapy will help me maintain my bone health and avoid the need for pharmaceutical osteoperosis interventions like Forteo.





[1] J Oral Maxillofac Surg. 2009 May;67(5 Suppl):35-43. doi:

Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the
jaws: clinical findings, assessment of risks, and preventive strategies.
Assael LA(1).
Author information: 
(1)Department of Oral and Maxillofacial Surgery, Oregon Health and Science
University, Portland, OR 97239, USA. assael@ohsu.edu
PURPOSE: Oral bisphosphonates are known to have potentially profound effects on
oral health. A review of the evidence supporting answers to key clinical
questions is necessary to assist surgeons in the care of their patients who are
receiving oral bisphosphonates.
MATERIALS AND METHODS: The literature is reviewed to address several questions,
ie, what is the risk of bisphosphonate-related osteonecrosis of the jaws (BRONJ) 
in my patient on oral bisphosphonates? Why are so few cases of BRONJ attributable
to oral bisphosphonate use? What is the importance of cofactors in the
development of osteonecrosis? How major a clinical problem is BRONJ, typically,
in the oral bisphosphonate patient? What dental procedures are associated with a 
risk of BRONJ? Are other findings apart from BRONJ of importance in the oral
bisphosphonate patient? Are there proven strategies to prevent BRONJ in the oral 
bisphosphonate patient? Should my patient discontinue the use of oral
bisphosphonates temporarily or permanently?
RESULTS: A review of the evidence offers information that will help in clinical
decision-making. In general, the risk of BRONJ is between 1 in 10,000 and 1 in
100,000, but may increase to 1 in 300 after dental extraction. The great majority
of BRONJ cases will likely remain in the intravenous population. Cofactors have
not been firmly established, although smoking, steroid use, anemia, hypoxemia,
diabetes, infection, and immune deficiency may be important. Rarely does BRONJ in
the oral bisphosphonate patient appear to progress beyond stage 2, and many cases
reverse with discontinuation of oral medication. Extraction is the only dental
procedure shown to increase the risk of BRONJ. Dental implant therapy should be
used with caution in the oral bisphosphonate patient. The benefits and risks of
oral bisphosphonate use must be weighed individually and in consultation with the
prescribing physician, before determining the need for temporary or permanent
cessation of medication.
CONCLUSION: Emerging evidence supports clinical decisions in favor of the oral
and maxillofacial surgery patient taking oral bisphosphonates.
PMID: 19371813


[2] Osteoporos Int. 2010 Jun;21(6):1041-5. doi: 10.1007/s00198-009-1004-0. Epub 2009
Jul 14.

Of mice and men: divergent risks of teriparatide-induced osteosarcoma.

Subbiah V(1), Madsen VS, Raymond AK, Benjamin RS, Ludwig JA.

Author information:
(1)Department of Sarcoma Medical Oncology, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

SUMMARY: Since approval by the U.S. Food and Drug Administration (FDA) in
December 2002, teriparatide (recombinant 1-34 PTH; Forteo) has been safely used
by more than 430,000 patients. Prior to FDA approval, however, there was concern
that teriparatide might increase the risk for patients to develop osteosarcoma,
as almost 45% of the rats treated with this drug at the highest-tested dose level
developed this aggressive form of bone cancer. Balancing the proven benefits of
teriparatide shown by clinical trials with the theoretical risk for
teriparatide-induced human osteosarcoma, the FDA mandated both a 'black-box'
warning of this potential side-effect and a company-sponsored postmarketing
surveillance program. As a participating institute of that surveillance program,
we report upon the second person with potential teriparatide-induced
osteosarcoma, in this case, complicated by a history of pelvic radiation.
INTRODUCTION: Given the theoretic risk of the drug teriparatide and the known
risk of radiation in inducing osteosarcoma, we raise the issue of whether
teriparatide magnified the risk of radiation-induced osteosarcoma in our patient
and try to determine which factor played the predominant role in the development
of his disease.
METHODS: We analyzed preclinical rat data, human clinical experience with
teriparatide, and our patient's clinical history to assess the human risk of
teriparatide and radiation exposure.
RESULTS: After the first case of suspected osteosarcoma was reported in December
2005, we encountered a second possible teriparatide-induced osteosarcoma less
than a year later. Review of the preclinical animal data would suggest that
teriparatide is safe for human use when used as recommended by the manufacturer.
Given the location of the sarcoma within the field of radiation and the limited
exposure to teriparatide before diagnosis, it is unlikely that teriparatide
played the predominant role in the emergence of this patient's osteosarcoma. We
cannot, however, exclude the possibility that teriparatide magnified the
carcinogenic effect of radiation therapy to induce the osteosarcoma.
CONCLUSION: Of more than 430,000 persons who have received teriparatide for
treatment of severe osteoporosis, we report the second patient to develop
osteosarcoma. Although teriparatide reduces osteoporosis-related fractures in
select patient populations, important contraindications, such as prior radiation
exposure, should be considered before use.

PMID: 19597911



[3] J Bone Miner Res. 2012 Dec;27(12):2429-37. doi: 10.1002/jbmr.1768.

The US postmarketing surveillance study of adult osteosarcoma and teriparatide:
study design and findings from the first 7 years.

Andrews EB(1), Gilsenan AW, Midkiff K, Sherrill B, Wu Y, Mann BH, Masica D.

Author information:
(1)RTI Health Solutions, Research Triangle Park, NC 27709, USA. eandrews@rti.org

The Osteosarcoma Surveillance Study, an ongoing 15-year surveillance study
initiated in 2003, is a postmarketing commitment to the United States (US) Food
and Drug Administration to evaluate a potential association between teriparatide,
rhPTH(1-34), a recombinant human parathyroid hormone analog (self-injectable
medication to treat osteoporosis), and development of osteosarcoma in response to
a finding from preclinical (animal) studies. Incident cases of primary
osteosarcoma diagnosed in adults (aged ≥40 years) on or after January 1, 2003,
are identified through population-based state, regional, and comprehensive cancer
center registries in the US. Information on possible prior treatment with
teriparatide, on demographics, and on risk factors is ascertained by patient or
proxy telephone interview after patient consent. Between June 2004 and September
30, 2011, 1448 cases (diagnosed 2003 to 2009) were identified by participating
cancer registries (estimated to be 62% of all adult cases in the US for that time
period); 549 patients or proxies were interviewed. Interviewed patients were
similar to noninterviewed patients with regard to mean age, sex, race, and
geographical distribution and tumor type and site of tumor. Mean age of those
interviewed was 61 years, 46% were female, 86% were white, and 77% were alive
when the case was reported to the study investigators. Data collected in the
study provide descriptive information on a large number of adults with
osteosarcoma, an uncommon malignant bone tumor. After 7 years of the study, there
were no osteosarcoma patients who had a prior history of teriparatide treatment.
Thus, approximately halfway through this 15-year study, the study has not
detected a pattern indicative of a causal association between teriparatide
treatment and osteosarcoma in humans.

Copyright © 2012 American Society for Bone and Mineral Research.

PMCID: PMC3546381
PMID: 22991313



[4] Toxicol Pathol. 2004 Jul-Aug;32(4):426-38.

Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on
duration of treatment and dose.
Vahle JL(1), Long GG, Sandusky G, Westmore M, Ma YL, Sato M.
Author information: 
(1)Lilly Research Laboratories, Greenfield, Indiana, USA. jvahle@lilly.com
A long-term study was conducted in female F344 rats to determine the relative
importance of dose, treatment duration, and age at initiation of treatment on the
incidence of teriparatide [rhPTH[1-34)]-induced bone proliferative lesions.
Treatment groups consisted of different combinations of dose (0, 5, or 30
microg/kg/d), treatment duration (6, 20, or 24 months) and age at initiation of
treatment (2 or 6 months of age). The primary endpoints were the incidence of
bone neoplasms and effects on bone mass and structure as evaluated by
quantitative computed tomography and histomorphometery. Significant increases in 
the incidence of bone tumors (osteoma, osteoblastoma, and osteosarcoma) occurred 
in rats treated with 30 microg/kg for 20 or 24 months. No neoplasms were found
when the 5 microg/kg treatment was initiated at 6 months of age and continued for
either 6 or 20 months (up to 70% of life span). This treatment regimen defined a 
"no-effect" dose for neoplasm formation that nevertheless resulted in substantial
increases in bone mass. These results demonstrate that treatment duration and
administered dose are the most important factors in the teriparatide-induced bone
tumors in rats.
PMID: 15204966
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Hi Dean!


If your nails are hard, you probably don't have osteoporosis.


Concerning side effects of Forteo:  the daily injection is "a piece of cake" (metaphorically :)xyz).  Those side effects are exaggerated (as they always are for any medication -- the technical term for this procedure by Drug manufacturers is "covering your ass").


But, if you don't need it, don't take it!




  --  Saul

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