Bisphosphonates like zoledronate (or teriparatide/romosozumab/abaloparatide) for low bone density?

[InquilineKea]

They seem neutral to very mildly helpful for heart disease risk. They also seem way higher upside/downside than strontium (strontium = deceptive alignment).

More here: https://www.rapamycin.news/t/medications-for-low-bone-density-bisphosphonates-teriparatide-estrogens-potential-long-term-effects/4740/28

Skeleton turns over in roughly ~10 years.

There are weird rare side effects, but they're just scary because they're so weird (despite being so rare).

Anyhow, Asians have lower BMD but don't have increased fracture risk.

tl;dr: I did my research, this is the perfect excuse for me to get a Rx for zoledronate (which is also, oddly, a geroprotector) - problem easily solved. I have not suffered anything from my low BMD, but I think (after seeing my results) it's wise for me to not do particularly risky kinds of exercise until I can get my BMD up.

[this is super-relevant for many of us b/c CR *and* veganism both lower bone mineral density, to which there is an easy fix if more of you did DEXA scans..]

Edited March 18, 2023 by InquilineKea

[Mike Lustgarten]

Weight-bearing exercise will likely be best for BMD. Have you started that?

[Ron Put]

4 minutes ago, Mike Lustgarten said:

Weight-bearing exercise will likely be best for BMD. Have you started that?

What Mike said.

I forget, how old are you, Alex? Methinks most healthy people should stay away from pills that may/are likely to cause more harm than good in the long run. At some point, science will come up with a way to extend health-span and/or lifespan, but nothing I am aware of yet fits the bill today, IMO.

Eat whole (plant) foods, in moderation, go for a run/hike outdoors, sleep well and yes, don't forget to do some wight-bearing exercises, and unless you have some unique issues, you will do better than most.

[IgorF]

The side effects are not just weird, given the calcium role in the lower-level cell machinery and intracellular communication networks I would say - no one wants to intervene with it having no serious reasons to do it.

There is also an unexpected (for me) battle against the the major drugs of the group mentioned, it is described in the book https://www.amazon.com/Oral-Intravenous-Bisphosphonate-Induced-Osteonecrosis/dp/0867155108

I checked it briefly and will probably try to read it, just to have more depth in my understanding of the topic.

Maybe it is outdated a bit and the things are not like described but the fact of its existence rings some bells.

 

Br,

Igor

Edited February 19, 2023 by IgorF

[IgorF]

Just read a bit, the book is good but it is rather a medical book, not for general reading.

A brief on the way bisphosphonates work:

- they are attaching to the bones surfaces where osteoclasts are usually active in bone destruction

- they are killing osteoclasts

thus the effect is that less bones are destroyed (and less calcium comes into circulation)

The known side effects:

- bones at the places where their natural turnover is the highest (jaw parts) will accumulate dead bones forming cells and after some times a quantity will become a quality - necrosis well-described in the literature

- bones will become more fragile in unusual places - there are described fractures, specific for patients after several years on such drugs

 

I did not searched for the possible explanation of the idea that these drugs could have some effect for heart desease but a possible ways could be:

- less calcium in circulation - less calcification in the plaques (this is not the reason but an indicator, perhaps a correlation and not causation)

- osteoclast-macrophages relativity/ancestry - maybe the drugs are sporadically killing entrapped into tha plaques macrophages when hitting them in the circulation

Or maybe these guesses are too simple, and the possible way is different.

 

In any case, I would say - these drugs are to be avoided (unless are prescribed and seriously discussed with doctors) as well as working in phosphorus mines where similar things were discovered a century before the drugs were invented.

 

 

Br,

Igor

[Saul]

Biphosphonates don't build bone; they only slow the normal remodeling process by killing some of your osteoclasts.  This leaves more of your old bone in place, without making new bone.  Old bone develops cracks; the quality gets worse and worse with time.  You might eventually develop fractures -- e.g., if you bash into something or fall.

There are three drugs that actually build bone that are available.  The oldest, and also the one that I take, is Forteo.  It is the first portion of the human parathyroid hormone, and binds to the same sites as the parathyroid hormone.  It is taken by subcutaneous injection, once daily.

  --  Saul

[InquilineKea]

What are the other two drugs? How do you get a Forteo/Teriparatide prescription, esp if you are not a postmenopausal woman? (I do have low bone density but I'm at a young age so I wonder if I could get one)..

Well, since I am in Massachusetts, I can try to see https://www.massgeneral.org/endocrinology/endocrine-unit/treatments-and-services/bone-density

(edit - called them - they're WAY overbooked to August)

or https://www.bidmc.org/centers-and-departments/endocrinology-diabetes-and-metabolism/services/osteoporosis-prevention-and-treatment-center

hopefully they would be enlightened enough to Rx Forteo rather than bisphosphonates

BONE DENSITOMETRY:
Technical Limitations: None.
Technique: Central DXA bone densitometry was performed on a Hologic
QDR 4500 Discovery system.
Findings
DXA DATA
Region _____________________________ AP spine (L1-L4)
Exam Date __________________________ 02/02/2021
BMD (g/cm2) ________________________ 0.636
T-score ____________________________ -4.1
Region _____________________________ Femoral Neck (Left)
Exam Date __________________________ 02/02/2021
BMD (g/cm2) ________________________ 0.522
T-score ____________________________ -2.8
Region _____________________________ Total Hip (Left)
Exam Date __________________________ 02/02/2021
BMD (g/cm2) ________________________ 0.717
T-score ____________________________ -2.0
In the absence of major risk factor, W.H.O. classification does not
strictly apply to this patient.
Impression: Individual Z-score of -2.0 or less is considered to have
low bone density for age.

...this is outlier low for any gender at *any* age... Wow.. and I should be extra-cautious whenever jumping down multiple flights of stairs...

• Quote

  Example: When Peter’s looking at a 35-year-old patient and their Z-Score is already -1.0, that’s just as concerning as if their OGTT shows very elevated postprandial glucose and insulin levels

   

Edited March 21, 2023 by InquilineKea

[Saul]

23 hours ago, InquilineKea said:

What are the other two drugs

Tymlos:  this is a peptide identical to the first part of the PTHrP (Parathyroid Resembling Protein (created by exercising muscles); Forteo is the first part of PTH.  Both PTHrP and PTH bing to the same sites.

The third (true) bone building druge is relatively new:  Evenity is a monoclonal antibody, that blocks sclerostin -- sclerostin regulates osteoblasts; it (partially) blocks osteoblast synthesis; so blocking it increases osteoblast production, and therefore builds new bone.

Forteo and Tymlos work by binding to the sme sites as PTH hormone (human PTH hormone also has the same bone building effects as Forteo and Tymlos -- but you can't buy it.  Why? no company can patent a hormone; so no company mfg it would make money).

It appears that Evenity builds more bone than Forteo/Tymlos. 

  --  Saul

P.S.:  All three drugs are very expensive. 

 

[InquilineKea]

Quote

 

Hi, Alex-

 

I hope you are well. I got the result of your bone density scan which showed osteoporosis and low bone density. This means you are at increased risk of fragility fractures. I would like you to see one of our endocrine specialists to discuss treatment for this and placed a referral. I also would like you to get some additional testing done (testosterone level, phosphorous, thyroid) before you see one of our endocrinologists.

 

Yeah! This is an indication that, if you have, isn't hard to get early medical treatment for, so I don't view this as too much of a concern downstream of calorie restriction/veg*nism

BMD                     BMD Change        BMD Change

Skeletal Site  (g/cm2) T-score Z-score Since Prior Scan  Since First Scan

=============  ======= ======= ======= ================  ================

PA Spine       0.711   -3.1    -3.5    ---               ---

Total Hip/Left 0.692   -2.1    -2.1    ---               ---

Fem Neck/Left  0.539   -2.8    -2.6    ---               ---

=============  ======= ======= ======= ================  ================

...Holy shit, BMD of ~3SDs below the mean... hip decreased, spine increased, femoral neck increased (but in all cases, barely)

====

Quote

The underlying problem with osteoporosis is excessive bone breakdown. Anti-resorptive medications Will slow bone break down, allowing for increased bone density over time. For bisphosphonates, This is safe and effective for between three and five years. For Prolia- our 10-year freedom extension trial showed that it was safe and effective for much longer durations. Taking a bisphosphonate and slowing bone resorption for too long can allow for an accumulation of micro damage within bone and may increase the risk of exceptionally rare stress fractures. The risk is 1 in 10s of thousands of taken for 5 years or less. Compare that to the risk of hip fractures (1 in 8 women), which carries a 1 in 5 chance of death within 1 year… again, if bisphosphonates are taken appropriately with a drug holiday every 3-5 years, these are reasonably effective meds.

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Similarly to bisphosphonates, denosumab appears to be implicated in increasing the risk of osteonecrosis of the jaw (ONJ) following extraction of teeth or oral surgical procedures but, unlike bisphosphonate, the risk declines to zero approximately 6 months after injection

https://www.healio.com/news/endocrinology/20220329/risk-for-osteonecrosis-of-the-jaw-higher-with-denosumab-vs-bisphosphonates

https://www.reddit.com/user/bonebuilder12/

Quote

 

Nutrition (building blocks for healthy bone), weight bearing exercise (stimulus- see wolffs law), and a medication that allows you to build bone faster than it is broken down. For those who are young with fairly severe osteoporosis, nutrition and exercise alone will slow further bone loss, but won’t rebuild what’s been lost. Sure, some who were very sedentary or had significant nutritional deficiencies at baseline will see a small bump in bone density for a few years (think correcting underlying osteomalacia from severe vitamin d deficiency), but this will not be preserved and all longer term studies show a continual loss of bone density with nutrition and exercise alone.

From research and personal experience, 1 year Evenity followed by 2 years of a bisphosphonate followed by a drug holiday and monitoring is a very safe and effective plan that should improve spine bmd by 18-20%, which is nearly 2 standard deviations on the T-score scale.

 

 

Edited March 16, 2023 by InquilineKea

[InquilineKea]

https://en.wikipedia.org/wiki/Zoledronic_acid

Wow, once per year too...

I could just wait to see more data come out (I'm already surprised at how long it took for me to start taking action on this but maybe it's okay b/c I wouldn't want to rush to bisphosphonates too early)

Relative potency^[26]

Bisphosphonate	Relative potency
Etidronate	1
Tiludronate	10
Pamidronate	100
Alendronate	100-500
Ibandronate	500-1000
Risedronate	1000
Zoledronate	5000

Edited March 13, 2023 by InquilineKea

[InquilineKea]

Quote

 

The hip BMD response using teriparatide in prior bisphosphonates users was less than expected. There are possible mechanistic reasons for these findings. With long-term bisphosphonate use, bone turnover is inhibited, and cortical bone is highly mineralized. At cortical sites, such as the hip, teriparatide induces absorption of old bone matrix and apposition of new bone matrix not yet fully mineralized (8, 33, 34). A transient fall in BMD can be seen at the beginning of teriparatide therapy as a result of the resorption of highly mineralized old bone and increased cortical porosity (8, 35, 36). BMD then slowly increases with ongoing treatment as new bone fully mineralizes. In our patients who had a median duration of prior bisphosphonate use of 7 years, BMD gained by new bone mineralization may be offset by old bone resorption for at least the first year. In contrast, denosumab binds and inhibits the receptor activator of the nuclear factor-κB ligand to achieve extensive suppression of bone turnover and increases BMD at all skeletal sites (37). The switch to denosumab increases BMD even after long-term antiresorptive therapy (38). A transition to denosumab from alendronate produced greater BMD increase at all measured anatomic sites and a further reduction in biochemical markers of bone turnover (38).

The poor hip BMD response in patients switching from bisphosphonates to teriparatide highlights the importance of a drug sequence when using anabolic and antiresorptive agents (7, 9, 16, 39–41). Cosman et al. (7) summarized BMD changes at the hip in various published clinical trials investigating the effects of teriparatide when used after an antiresorptive agent. BMD, at the hip, fell below baseline values for the first 12 months after switching, resulting a decrease of −2.7 to −0.3% in total hip BMD, but returned to baseline at 18 months (−1.7%–0.9%) and almost increased above baseline by 24 months (−0.7% to 2.9%) (8–10, 42, 43). Our study showed similar BMD trajectories: hip BMD dropped for the first 12 months and then returned to the baseline level. As the switch to teriparatide in prior bisphosphonate-treated patients does not achieve optimal BMD gain at all sites, and teriparatide can only be used for 24 months, this routinely used strategy needs examination.

To maximize the treatment effect, substantial data suggest use of teriparatide before bisphosphonates (44–46). In one study, teriparatide followed by bisphosphonates, had better BMD gains than bisphosphonates followed by teriparatide (47). Over a period of 19 to 24 months, teriparatide achieved an average gain of ∼3% in the hip area (total hip and femoral neck). After teriparatide, the transition to a bisphosphonate led to a 2% additional increase in the hip area after 1 year (46). We evaluated prescription patterns in our study population and observed that teriparatide followed by bisphosphonates, was rarely used. The most widely used pattern in the last decade at Partners HealthCare was bisphosphonates followed by teriparatide. We examined the BMD increase profile of this pattern and did not identify a relative gain in BMD during the 2-year treatment compared with teriparatide followed with antiresorptive agents in a prior study (46). Thus, in patients who are likely to require more than one drug, previous sequential studies (8–10, 42, 46, 48) and our results suggest initial use of teriparatide, followed by an antiresorptive, as an alternative choice to achieve maximal gains in BMD (41).

 

 

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osteoclast’s resorptive capacity, and preventing osteoclast formation.[5] They have a high affinity for bone minerals and accumulate mainly in the sites of osteoclast activity.[5] Without resorption and new bone formation, old bone survives beyond its lifespan, and its capillary network is not maintained, leading to avascular necrosis of the jaw. Also, high potency biphosphonates can lead to necrosis by the toxicity of soft tissue and bone cells, further complicated by infection.[6] Due to altered wound healing, delayed epithelial closure of a mucosal opening in the mouth leads to chronic infection and the necrosis of bone.[7] Osteonecrosis develops in the jaw because this bone has a higher remodeling rate than other bones, making it more prone to the effect of bisphosphonates.

Go to:

Epidemiology

Intravenous (IV) Versus Oral Biphosphonates

Osteonecrosis of the jaw is mainly reported with the use of more potent nitrogen-containing BPs like pamidronate and zoledronic acid. However, the incidence is higher with the latter - zoledronic acid causes a higher antiresorptive activity, leading to decreased bone turnover.[8]

Oral biphosphonates rarely cause osteonecrosis of the jaw. They are less aggressive than intravenous BP, and the osteonecrosis caused by oral BP responds better to treatment. Oral BPs are less liposoluble, limiting their intestinal absorption, resulting in a lower accumulation in the bone.[9]

Dose and Duration

The incidence of osteonecrotic events increases with a higher dose of potent BPs administered for a longer duration.[10][11][12][13][14] The risk ranges from greater than 1% at 12 months to 11% after four years of treatment - taking zoledronic acid alone increases the risk of osteonecrosis to 21% after the third year. Due to the slow accumulation of oral BPs, no clinically exposed bone appears until after 3-year treatment, and incidence and severity increase with each additional year of use.

 

 

https://www.health.harvard.edu/womens-health/osteoporosis-drugs-which-one-is-right-for-you

https://eor.bioscientifica.com/view/journals/eor/3/9/2058-5241.3.170070.xml

Edited March 14, 2023 by InquilineKea

[InquilineKea]

https://www.sheffield.ac.uk/news/nr/osteoporsis_drugs_can_increase_risk_of_rare_fractures-1.902385

• Asian women had approximately five times the risk of atypical ‘stress’ fractures with prolonged bisphosphonate use compare to white women

Asians have lower porosity combined with thicker BMD

Quote

 

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

 

Quote

Public concern has led to a >50% decrease in BP usage. AFFs are rare: for each AFF, >1200 fractures, including 135 hip fractures, are prevented. Case definition criteria were updated by the American Society of Bone and Mineral Research in 2014. Many epidemiologic studies have been reported, and although methodologically challenging, generally support a BP-AFF association. However, the magnitude of the association between BPs and AFFs is uncertain: estimates of relative risk for AFFs among BP users vs nonusers range from 1 to 65 with a meta-analysis estimate of 1.7. Although mechanistic studies have proposed several hypotheses explaining how BPs might decrease bone strength, AFF pathogenesis remains uncertain and cannot explain the paradox of efficacy of reduction of common fractures while increasing risk for rare fractures at one site. There are several consistent risk factors, including Asian race (in North America), femoral bowing, and glucocorticoid use, whereas others remain unclear

 

Quote

 

The 2019 Endocrine Society clinical practice guidelines included patient profiles representing examples of high and very high fracture risk⁵:

• High risk: T-score of minus 2.5 or below, or prior hip or vertebral fracture, or high fracture probability by the fracture risk assessment tool (FRAX) (10-year probability of major osteoporotic fracture ≥ 20%, or 10-year probability of hip fracture ≥ 3%)

• Very high risk: T-score of minus 2.5 or below and 1 or more fractures, or multiple vertebral fractures, or severe vertebral fracture.

The Endocrine Society guidelines suggest that anabolic therapy with teriparatide or abaloparatide be considered the first-line for treatment for up to 2 years in postmenopausal women with osteoporosis who are at very high risk of fracture.⁵

For initial therapy in patients at high risk, there is evidence that teriparatide should be started first, followed by an antiresorptive agent (eg, bisphosphonate, estrogen, selective estrogen receptor modulator, calcitonin, denosumab) because the bone formation effects of teriparatide are blunted by initiating therapy with an antiresorptive agent. Thus, the sequence of treatment is important.^6,7

 

 

Edited March 14, 2023 by InquilineKea

[Saul]

biphosphonates and/or prolia are a bad idea (unless you can't afford better treatment).  All of these treatments slow bone remodelling; they result in you retaining most of your old bone, but they don't build new bone -- you're left with fracture prone old week bone.

There are three available medications that actually build new, healthy bone.  Two of them are similar -- one, Forteo, is a peptide that is the first part of the parathyroid hormone; the second, Tymlos, is a peptide of parathyroid hormone resembling protein (PTHRP); both bind to the same sites, and stimulate osteoclast formation, which builds new healthy bone.

The third is a brand new treatment, Evenity -- it is a monoclonal antibody, that interferes with the normal functioning of the hormone sclerotsin -- sclerotsin stimulates osteoclasts and suppresses osteoblasts -- so Evenity results in more osteoclasts, less osteoblasts -- a win-win situation.

All three of these drugs are VERY expensive; and it's hard to get insurance to cover them.

I take Forteo once weekly (I used to take it daily -- but insurance cut me off, so I have to pay for the expensive drug myself).

It works very well.

  --  Saul

[InquilineKea]

How has Forteo changed your BMD - like how long does it take to get a response? Is there a huge difference between once-per-day and once-per-week?

[IgorF]

The bone quality topic is not just about BMD, it also is about structure and microstructure and more things.

A good primer on topic could be

 

In few words - a doctor who understands the whole picture decides what and how to prescribe to manage the risks. It is not a self decision of a pacient if increasing the density is a desirable thing or a main target.

 

There is only one good recipe known for bone quality in the young and perhaps until middle age (until 35 +- maybe a bit later) - a good diet with enough protein, calcium, d3+k2 and excercises that are creating tensions at different angles, so not only weights but also yoga, taichi/qigong and dancing sections. Later the same things will help to avoid losing bone mass and quality as long as possible.

Drugs were developed to manage the risks of fractures, they will not be even close to the natural way of building good bones. So for those who still can do it naturally it is a strange thing to first decide to do CR severe enough to make one not healthy from bones perspective (and others perhaps) and then to search for a drug (not designed at first place for such usage) that can help regain 10% of lost abilities.

Sorry for saying it this way but that is probably will be said by any doctor if will ever be asked giving all the circumstances surrounding such a strange (for them) question.

 

 

Br,

Igor

Edited March 14, 2023 by IgorF

[Saul]

13 hours ago, InquilineKea said:

How has Forteo changed your BMD - like how long does it take to get a response? Is there a huge difference between once-per-day and once-per-week?

Probably over 20 years; and yes, my BMD has been improving.

  --  Saul

[BrianA]

ran across this today

 

The Bisphosphonate Zoledronate as a Senolytic Drug

https://www.fightaging.org/archives/2023/03/the-bisphosphonate-zoledronate-as-a-senolytic-drug/

 

 

[InquilineKea]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832316/

Chances of atypical femoral fracture of BPs are way less after 1 to 2 years of discontinuation. I know being Asian increases the relative risk by like 5-8 times, but EVEN if Asian, the overall reduction in risk in other fractures still way outweighs increased risk of AFFs.

https://www.lifespan.io/news/life-extension-drug-discovered-by-accident/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179998/

https://pubmed.ncbi.nlm.nih.gov/33559705/

Holy shit - this decreases cholesterol + LDL + TGs (by being an inhibitor of melavonate pathway) - prolly decreases dolichol too

OK, I DEFINITELY am going for zoledronate then. My insurance will only cover Forteo if other treatments (like BPs) don't work first.

lol, my diet led to my osteoporosis, but this may be net-good for my longevity because it was THE excuse to put me on zoledronate

Edited March 15, 2023 by InquilineKea

[Sibiriak]

On 3/14/2023 at 1:49 PM, IgorF said:

Drugs were developed to manage the risks of fractures, they will not be even close to the natural way of building good bones.

So for those who still can do it naturally it is a strange thing to first decide to do CR severe enough to make one not healthy from bones perspective (and others perhaps) and then to search for a drug (not designed at first place for such usage) that can help regain 10% of lost abilities.

 

Well-stated!   Thanks for another excellent post.

[InquilineKea]

Asians have lower bone densities *and* don't have increased fracture risk: https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1002/jbmr.1939

https://www.webmd.com/osteoporosis/features/newer-osteoporosis-treatments-build-stronger-bones

Hm increases aren't huge. Bisphosphonates increase by like 6-8%, and Forteo by 16-18%? Maybe one needs both

Quote

From research and personal experience, 1 year Evenity followed by 2 years of a bisphosphonate followed by a drug holiday and monitoring is a very safe and effective plan that should improve spine bmd by 18-20%, which is nearly 2 standard deviations on the T-score scale.

 

Edited March 16, 2023 by InquilineKea

[Saul]

Evenity is a very powerful bone growth drug; it's also VERY expensive.  So drug companies, if they'l pay for Evenity for one year (good luck!) will only do so for one year; the biphosphonate is to try to hold onto the bone growth you've gottrn in that year, as much as possible -- it doesn't build new bone.

 

  --  Saul

[InquilineKea]

Just saw an endocrinologist. They were reluctant to prescribe, b/c "low bone density" in males under 50 is *not* osteoporosis (but it may be difficult to obtain insurance coverage for this). They'll talk to my PCP about what my PCP would do.

They noted how unusual it is for younger males to seek this (but they also said they were "very by the book"). I might want to try someone else, but I don't know if the chances of succeeding are high.

Tbf, part of the reason why I want this is that I want an excuse to get a zoledronate Rx (b/c zoledronate has now shown to be a geroprotector on other dimensions), but this now seems like a distant possibility unless I find the right doctor, and then it may be expensive, and zoledronate is not the most important geroprotector though it *is* a surprising one.

 

Quote

 

Age is a critical risk factor

More than 3 decades ago, a seminal study found that age is a major risk factor for fracture, independent of bone density.²⁷ With aging, fracture rates rise exponentially as bone density decreases. Fractures are less likely to occur in younger people than in older people, even with similar bone density measurements.²⁸ Clinical data show that this paradox reflects age-dependent microarchitecture degradation. As a result, a young patient with low bone density may not be at high risk for fracture unless other clinical factors are present, and an older patient with nonosteoporotic T-scores could be at high risk for fracture because of other clinical risk factors.

 

 

Edited May 4, 2023 by InquilineKea

[Saul]

Yeah, that's no surprise.  What you don't understand is that most osteoporotics do not take drugs that BUILD NEW BONE (e.g. teriparitide, evenity), but drugs that SLOW DOWN BONE REMODELLING (e.g., biphophonates, Prolia).  This results in thicker bone -- but full of flaws, since remodelling is slowed.

Actually, drugs like Forteo (teriparitide) sapeed up remodelling, while building new bone.

  --  Saul

 

[InquilineKea]

https://www.bonescore.com/patients/