Medications for low bone density (bisphosphonates LIKE zoledronate)? Potential long term effects?

The effects of teriparatide and bisphosphonates on new fract... : Medicine teriparatide seems superior

Also like google bisphosphonates

Google strontium too (the people at are skeptical)

Among participants with low bone density, the multivariable adjusted relative risk for an incident kidney stone for bisphosphonate users was 0.68 (95% CI, 0.48 to 0.98). In the cross-sectional analysis of 24-hour urine calcium excretion, the multivariable adjusted mean difference in 24-hour calcium was 10 mg/d (95% CI, 1 to 19) higher for participants with history of low bone density. However, among participants with history of low bone density, there was no association between bisphosphonate use and 24-hour calcium with multivariable adjusted mean difference in 24-hour calcium of -2 mg/d (95% CI, -25 to 20).


Low bone density is an independent risk factor for incident kidney stone and is associated with higher 24-hour urine calcium excretion. Among participants with low bone density, bisphosphonate use was associated with lower risk of incident kidney stone but was not independently associated with 24-hour urine calcium excretion.

Once bisphosphonates are in bone, they have a very long elimination half-life that can exceed ten years.[35]

Hmm, these are all listed as rare.

Side Effects

Side effects to oral bisphosphonates include: muscle cramps/pain, difficulty swallowing, heartburn, abdominal pain, nausea, headache, and/or rash. There is a rare risk of developing jaw or tooth pain, called osteonecrosis of the jaw. It is typically associated with trauma to the jaw (tooth extraction), history of malignancy and/or infections while on bisphosphonate therapy. It is recommended you have a good dental exam prior to starting these medications. Notify your doctor is you develop side effects to zoledronic acid include low blood pressure, dizziness, fatigue, headaches, muscle pain, weakness, gastrointestinal symptoms (nausea and constipation), fever, and/or rash. These side effects may last 1-2 days and up to 10-12 days after your infusion.

For either oral or intravenous medications, there is a rare risk of developing a jaw or tooth problem, called osteonecrosis of the jaw. Osteonecrosis of the jaw is typically associated with an invasive procedure to the jaw (tooth extraction) or history of malignancy and/or dental infections while on bisphosphonate therapy. It is recommended that you have a good dental exam prior to starting these medications. Notify your doctor if you develop side effects to the medications. Abnormal fractures of the femur (thigh bone, atypical femoral fracture) have been associated with bisphosphonate therapy, especially if the medication is taken for many years. An atypical femoral fracture often presents as thigh pain.

This just for bisphosphonates

“every 10 years we get new skeleton”

(the others that aren’t teriparatide or bisphosphonates have more worrisome side effects)

Osteoporosis is clearly a gene expression problem. Hence if you don’t solve that the system won’t work properly.

This paper explains it:

A positive correlation between serum IGF-1 level and BMD has been documented in women but not in men [4], in very old women [5], by others in men but not in women [6], and in healthy men [7]. Lower serum IGF-1 levels in women are reported to be correlated with the prevalence of fractures [8] and are strongly associated with an increased risk of osteoporotic fractures independently by BMD [9]. Recently, Ohlsson et al. [10] demonstrated that low serum IGF-1 levels were associated with an increased risk of fractures of about 40% and serum IGF-1 level could be clinically useful for assessing the risk of vertebral fractures [11]. Osteoporosis in postmenopausal women is due to estrogen (E) deficiency and having a high rate of bone remodeling with bone resorption exceeding bone formation [12]. The E deficiency is critical to the pathogenesis of osteoporosis in men and in women and the frequency of GH secretion is decreased in the amplitude with sex hormone reduction [13]. In young men the most significant hormonal determinants of the BMD of the hip and of the cortical thickness of the femoral neck are 17β-estradiol and IGF-1 while in aged men (over 60 years) the BMD was not correlated with IGF-1 at any site but only at 17β-estradiol [14]. It has been documented extensively that E is one of the factors regulating the expression of IGF-1 in maintaining skeletal integrity [15, 16]. The IGF-1 plays a central role in cellular growth, differentiation, survival, and cell cycle progression [17] and IGF-1 level is necessary for the proper acquisition of peak bone mass; furthermore GH protects against ovariectomy-induced bone loss [18]. Despite the evident anabolic effect of GH/IGF-1 on bone some conflicting clinical studies are evident. The aim of the present review is to evaluate the clinical studies published in the literature on the effect of GH and IGF-1 on bone metabolism in human subjects affected by severe osteoporosis and bone healing after surgery in non-GH deficient subjects.

In vitro studies suggested that ERα or ERβ translated mechanical forces into prosurvival signals in osteocytes and osteoblasts, independent of estrogens.65 Estradiol was shown to prevent osteocytes apoptosis and enhance the production of transforming growth factor-alpha which inhibits osteoclastic bone resorption.66 Thus, estrogens converted from testosterone in male could contribute to the anabolic action of osteocytes.

Design: Retrospective analyses of 40 middle-aged transsexuals treated with subcutaneous injections of gonadotropin-releasing hormone agonist every 4 weeks and oral 17-beta-estradiol-valerat 6 mg/day over two years until reassignment surgery.


Intervention: Dosage of 0.25 mg/d of micronized 17beta-estradiol (n = 83) or placebo (n = 84); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months.

Main outcome measures: The BMD of the hip, spine, wrist, and total body measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment.

you know, I do have an estradiol Rx. I lapsed because I don’t want to develop breasts, but I can take it from time to time. Now I’m convinced it’s a good idea.

The most promising supplements/small molecules for longevity - #16 by TongMD - akc-important-threads - LongevityBase Forum prodded me to finally look all this up. I don’t want to be masculinized - I hate it - I also hate everything associated with the IGF1/GH or testosterone axis. Estrogen is the thing I find tolerable, and tbf my lack of physical development past a certain stage might be correlated with my low bone density and otherwise super-childish features (though I want [and possibly need] the childish features).

Tbf, I fucking hate being male, and am spared from severe dysphoria because I can pass as a child.

In accordance, a study found that in women treated with a GnRH analogue, spironolactone therapy almost completely prevented the bone loss that is associated with these medications, whereas treatment with the selective AR antagonist flutamide had no such effect.[89][53] Other studies have also found an inverse relationship between spironolactone and decreased bone mineral density and bone fractures in men.[90][91] Estrogens are well known for maintaining and having positive effects on bone, and it has been suggested that the estrogenic activity of spironolactone may be involved in its positive effects on bone mineral density.[89][53][92] High levels of aldosterone have been associated with adverse bone changes, and so the antimineralocorticoid activity of spironolactone might partially or fully be responsible for these effects as a potential alternative explanation.[91]

In addition to potential direct interaction with the ER, spironolactone also has some indirect estrogenic activity, which it mediates via several actions, including:

  • By acting as an antiandrogen, as androgens can suppress both estrogen production and signaling (e.g., in the breasts).[29][93]
  • Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone.[84] Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.[94][95]
  • Enhancement of the rate of peripheral conversion of testosterone into estradiol, thus decreasing the ratio of circulating testosterone to estradiol.[75]

Spironolactone has been found to act as a reversible inhibitor of human 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2), albeit with weak potency (Ki = 0.25–2.4 μM; IC50 = 0.27–1.1 μM).[96][97][98][85] C7α thioalkyl derivatives of spironolactone like the 7α-thioethyl analogue were found to inhibit the enzyme with greater potency, suggesting that the actual active metabolites of spironolactone like 7α-TMS might be more potent inhibitors.[96][85] 17β-HSD2 is a key enzyme responsible for inactivation of estradiol into estrone in various tissues, and inhibition of 17β-HSD2 by spironolactone may be involved in the gynecomastia and altered ratio of circulating testosterone to estradiol associated with the medication.[84][99] Spironolactone has also been associated with positive effects on bone, and it is notable that 17β-HSD2 inhibitors are under investigation as potential novel treatments for osteoporosis due to their ability to prevent estradiol inactivation in this tissue.[100][101] In contrast to 17β-HSD2, spironolactone does not appear to inhibit 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) in vitro.[30]

There is suggestive evidence that Bisphosphonates could reduce cholesterol biosynthesis. The evidence is is neutral to slightly positive on its CV risk. So this is a good thing.

Since your mentioned Spironolactone, I’ll drop my question here: Does Spironolactone have any effect either inhibit or enhance when used with Rapamycin (Sirolimus)?

Spironolactone promotes autophagy via inhibiting PI3K/AKT/mTOR signalling pathway and reduce adhesive capacity damage in podocytes under mechanical stress

Do not take bisphosonates, absolute garbage which increase the risk of osteonecrosis after certain dental treatments for up to 10 years after stopping them. High protein diets especially the ones including full fat dairy and whey have been shown to safely (and deliciously) improve bone density and sarcopenia

Seems to be better than rapa (for rats), as shown in the pic (fewer holes -black spots).

Thus, treating OVX (ovariectomized) rats with Kae significantly improved bone microarchitecture and mass. The opposite trend was observed in the OVX + Kae + Rapa and OVX + Rapa groups: OVX rats treated with Kae + Rapa or Rapa only exhibited lower BV/TV, Tb.N and Tb.Th values and higher Tb.Sp and SMI values compared to the OVX + Kae group (P<0.05 vs. OVX + Kae).

From my work as a psychiatrist, it appears that Lithium may have benefits for increasing bone density.

Zamani A, Omrani GR, Nasab MM. Lithium’s effect on bone mineral density. Bone. 2009 Feb;44(2):331-4. doi: 10.1016/j.bone.2008.10.001. Epub 2008 Oct 18. PMID: 18992857.

1 Like

Good to know. Perhaps this is one of the mechanisms by which lithium provides life extension benefits.

You made me take look for other citations. I was surprised to find this:
“Lithium stimulates human bone marrow derived mesenchymal stem cell proliferation”

What are mesenchymal stem cells?

“What is the difference between stem cells and mesenchymal stem cells?
Human embryonic stem cells (hESCs) are characterized by their immortality and pluripotency. Human mesenchymal stem cells (hMSC), on the other hand, have limited self-renewal and differentiation capabilities.”

I consider this a must-read on the benefits of lithium supplementation.

Lithium stimulates human bone marrow derived mesenchymal stem cell proliferation through GSK-3β-dependent β-catenin/Wnt pathway activation


I think the longevity benefits of lithium lie around GSK-3β inhibition and the WNT pathway, but this is a pathway I don’t properly understand for now. We need better research on the appropriate serum and dosing levels for this, but we have a reasonable idea that it is probably in the lower part of the range from 1-5mg a day.

1 Like

I got some orotate last week and tried 5mg. This is what I used to use all the time just to help me chill. It used to work great. Then it started giving me headaches. Sort of delayed maybe 10 hours after I take it. I don’t tolerate it at all for some reason I can’t figure out.

Also possibly related is that any caffeine or related like chocolate does the same thing. I can’t even have a chocolate chip any more. For years now. Any Ideas at all what could do this?

For some reason, Kaiser Permanente recommended that I get a DXA Scan six years ago, age 64.

Your bone density T-score result is: -3.7. This means you have OSTEOPOROSIS .Further evaluation and treatment is recommended per Kaiser’s Guidelines to slow down bone loss and help prevent you from breaking a bone.”

I am (or was) an enthusiastic distance backpacker at that time, having hiked about 15,000 miles in the US over the course of the decade prior to that diagnosis. I fell down, hard, a lot, and banged up myself in all manner of ways, and never broke a bone. So I found it amusing that as a result of this diagnosis, I got rote recommendations about removing loose rugs, putting railings in the shower, and the like.

But it was concerning, and KP wanted me to start alendronate. Which I did, plus upping my calcium and vitamin D intake. (Tests didn’t find any genetic or other idiosyncratic explanation.)

A few months after starting the alendronate, I asked for another scan to measure progress. I was told no, because any improvement wouldn’t show up. Say what. How do I know if it’s doing any good? Apparently Kaiser was administering alendronate a large number of individuals, found that subsequent scans showed no improvement, so they stopped the treatment. And then they saw a noteworthy increase in fractures among those individuals. So there’s your evidence of effectiveness.

I took alendronate for 3-4 years, was supposed to go five years. But I lost interest. I never noticed any side effects.

I was freaked at first, but continued with my backpacking activity and retained my loose rugs. I think a good test of bone quality is to sit on a fabric foldable camp stool, have the fabric seat tear loose from the metal frame, and then immediately accelerate butt-first into the ground. Good stress test of the spine and pelvis. My tailbone was sore for several days, but otherwise no damage.

So maybe this says something about quality vs. quantity. Though I don’t really know was quality means here.

My 91yo mother in assisted living, fell down, broke her hip, therapy/put back in a. l., fell down again broke something again, and then while bedridden everything else shut down. Her z-scores for hip were around 2.1. Never reached the osteoporosis threshold, and was never given alendronate. Another testament to quality vs. quantity?.

What HAS largely terminated my extended backpacking is that in the last couple of years, I have become extremely sensitive to heat. Whereas I used to be able to tolerate heat quite well, hiking consecutive ten hours days in the spring time desert, when I go out in the desert sun now, I feel like I am being pan-fried. I assume this is age-related, but who knows. Came on rather quickly.


FWIW, my practitioner said that it takes years to notice a difference, so there isn’t any point to do the tests every year, much less every month.

I added natto & vit k after the first. The second said that one of my hips was a bit worse off, the other was the same. The tests were some number of years apart, don’t remember how many. They didn’t mercifully, say osteoporosis, but not perfect either.

Has anyone tried boron?

Yes, I take 5 mg. daily for the last few years. Supposed to help with arthritis and prostate. My Dad and uncles all got prostate cancer, not a club I wanted to join.

It has no side effects that I know of and costs very little, so picking up unknown coins in front of a tricycle.

I take 3mg daily. That aeems to be a standard quantity.