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

Supplements
#82

After 2+ years of my wife taking Life Extension Bone Restore Elite, her MD put her back on Fosamax after her last scan. I know some here have mentioned AlgaeCal but I hope to get som input from others here about it or anything additional going forward. Thanks all.

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#83

Phillipe, you can research using ChatGPT to find lots of good answers related to improving bone density and I have tried that. It’s likely better than word of mouth, but it’s time consuming when you don’t know what questions to ask. So, I searched YouTube for experts. I found one YouTube channel I like called “The Dr. Doug Show.” Dr. Doug is a real doctor who provides excellent information on bone health. The information is scattered among many, many presentattions because he can’t discuss everything in only one. Some of the presentations are superb, others not so much. And, you will encounter salesmanship from him because he does need to make some profit for his effort (which I do not mind). You will not find a single, simple answer from his presentations, but if you watch them regularly for a few weeks you’ll likely be better informed than your doctor. As an example, my doctor just prescribed Boniva and had a nurse call me to go and pick it up at the pharmacy. There was no prior discussion. It was simply what she and likely most other Docs do as first-line defense. Having researched osteonecrosis of the jaw years before I did not like that solution and did not follow it. An interesting note is that my current dental surgeon would not have accepted me as a patient had I taken a bisphosphonate.

Here is a decent presentation on The Dr Doug Show: https://www.youtube.com/watch?v=NNNWglG6kIA

Or, here is a link to his YouTube Channel: https://www.youtube.com/@Dr_DougLucas

I wish you the best of luck in your and your wife’s bone health journey. And, so far, it has been a journey for me because I’ve found no quick answers.

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#84

Jay,
I went to my (ex) gyn a few months ago
 and then a couple days later I got a call from the pharmacy that my rx for an osteoporosis medicine was ready (sound familiar!?).

She never discussed the various options nor did I agree to any. Needless to say, I told the pharmacist they could put it back on the shelf.

@Phillipe Algae Cal is hugely popular. I’ll note that someone here takes something very similar, but it was a lot less expensive.

FYI, I have heart disease and was told one of its ingredients, strontium, might add to my risk. It might be perfectly fine if you don’t have CVD risk, but I just wanted to point that out.

And grain of salt because I’m a novice on the topic, but I chose the Thorne brand of calcium because it’s dicalcium malate which means it does not need to be taken with a meal. Aside from the strontium, I do get the other algaecal ingredients in my other supplements.

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#85

FYI, strontium citrate or carbonate is of little value for bone health. You want strontium renalate, which is prescription only. However I would not want to be on strontium renalate for more than three years. I have recently again taken a look at bone health and bone generation, because I will soon have spinal surgery and bone fusion, so supplements are something I have looked at. Based on the literature I have elected to skip OTC strontium (citrate, carbonate).

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#86

CronosTempi, here is the ChatGPT summary of strontium renalate restrictions in the EU:

Strontium ranelate (Protelos/Osseor) — EU Restrictions Summary

  • 2013–2014: EMA restricted use due to increased risks of heart attack, blood clots, and cardiovascular events.
    • Allowed only for severe osteoporosis in patients who couldn’t use other treatments.
    • Contraindicated in anyone with existing cardiovascular disease or uncontrolled hypertension.
    • Required regular cardiovascular monitoring during treatment.
  • 2014: EMA’s safety committee recommended suspending the drug because the benefit-risk balance was no longer favorable.
  • 2017: The drug effectively disappeared from the market (no longer marketed).
  • 2020: The manufacturer requested and the EU granted full withdrawal of marketing authorization.

Bottom line: Strontium ranelate wasn’t instantly “banned,” but its use became so restricted due to cardiovascular risks that it was eventually withdrawn from the EU market entirely.

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#87

Short term strontium ranelate might still be of interest.

The Influence of Strontium on Bone Tissue Metabolism and Its Application in Osteoporosis Treatment

Longer term indeed there seem to be CVD issue, so for those folks with CV risk factors it’s something to avoid. But shorter term (up to 3 years), there might be use for it in the right circumstances. YMMV.

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#88
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#89

You may want to read more about these parathyroid analogs. Forteo and Tymlos are the two medications. My understanding is that you don’t just take the Bisphosphenate (reclast or zometa) for a short time. The most current practice that I am aware of is that you take Prolia, a monoclonal antibody that is a resorptive (like bisphosphenates) for a long time, or even forever after getting off the parathyroid drugs. The parathyroid drugs goose the bones into creating new bone, but that stops happening once you stop taking them, and then you go back to where you started, unless you turn on the antiresorptives. But the basic problem is: you are no longer making new bone any faster than you were before you started the parathyroid drugs. My cousin and sister both did the Forteo – and regretted it. And, should add that they were not told that they would have to stay on Prolia basically forever . . .

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#90

Short answer: no. “Bisphosphonates” is two mechanistically unrelated drug families sharing a name, and only one of them is even a candidate.

The split matters more than people realize. The non-nitrogen ones — clodronate, etidronate, tiludronate — get metabolized into non-hydrolyzable ATP analogs that poison osteoclast mitochondria. Clodronate doesn’t touch protein prenylation at all. PubMed The nitrogen-containing ones (alendronate, risedronate, pamidronate, zoledronate) inhibit farnesyl pyrophosphate synthase in the mevalonate pathway. ScienceDirect Every geroscience story runs through FPPS. So half the class is excluded a priori, and there’s a nice natural experiment buried in there: in melanoma lines, pamidronate and zoledronate kill, clodronate does nothing. nih Same skeletal target, opposite non-skeletal biology.

Within N-BPs it’s basically one drug: zoledronate. Partly potency, mostly pharmacokinetics — oral BPs have ~1% bioavailability and all of it goes to hydroxyapatite, so systemic tissue exposure is near-nil. Alendronate is mechanistically identical and probably can’t reach the concentrations that matter anywhere but bone. I’m fairly confident in that reasoning but it’s inference from PK, not a head-to-head trial.

Evidence state, honestly split:

  • Observational: mortality reductions of 25–60%. Almost certainly inflated. The tell is damning — one study found lower mortality within days of starting treatment. NCBI That’s healthy-adherer confounding wearing a lab coat.
  • RCTs in aggregate: null. Cummings’ 38-trial meta found no mortality effect; zoledronate specifically RR 0.88 (0.68–1.13). The Rheumatologist A 2025 meta reached the same conclusion and graded it high-quality. Ovid
  • The live signal is single-trial secondary endpoints: in Reid’s osteopenia trial, fewer MIs (HR 0.60), less cancer, a nonsignificant mortality trend. PubMed Exploratory. Plausible, not established.

The preclinical case — and the part press releases sand off. Bellantuono’s group showed zoledronate extended hMSC survival in culture, preserved osteogenic/adipogenic differentiation, reduced DNA damage foci, via mTOR inhibition. Warwick Research Archive Portal Then flies, which have no mineralized bone — an elegant design, since it dissociates osteo- from gero-protection. Lifespan extended, climbing improved, gut dysplasia reduced, FPPS-dependent, dFOXO-dependent. ResearchGate Headline: 14–18% median extension in females from middle age, rapamycin-range. Oxford Academic But the actual curves: 1 ”M helped males and not females lifelong, and 10 ”M lifelong hurt female survival. biorxiv Dose × sex × timing all flip the sign. Also — and I looked — I found no zoledronate result in the NIA ITP, and there’s a structural reason: the ITP tests orally-administered agents. The Jackson Laboratory The gold-standard mouse test can’t easily be run on an IV drug.

The thing I find most interesting. Zoledronate is proposed as a geroprotector while also producing, in bone, the closest thing to a drug-induced aging phenotype we have: atypical femoral fractures and ONJ — frozen remodeling, tissue that can’t clear its own microdamage. It’s a targeted cytotoxin repurposed as a cytoprotectant; the therapeutic window is the difference in uptake between osteoclasts and everything else. Its virtues as a bone drug (no absorption, no metabolism, glued to mineral) are precisely its disqualifications as a systemic geroprotector. Fix the pharmacology and you’ve built a statin.

“The stem cell kind” — I read this two ways and I’m ~60/40 on which you meant. If you mean which BP acts on stem cells: zoledronate, the MSC work above, and note MSCs there are a readout of aging, not a therapy. If you mean stem cell therapy for aging: separate field, weaker on lifespan, better than I expected on function — a phase 2b of allogeneic bone-marrow MSCs in frailty hit its primary endpoint, +63 m on 6-minute walk at 9 months. Cell Press Caveat: infused MSCs mostly don’t engraft; they’re immunomodulatory paracrine agents. Calling them stem cells is a naming artifact.

Which reading did you want? I’ll go deeper on either.

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#91

. Teriparatide’s gains are blunted if you’ve had bisphosphonates first, more at the hip than the spine, and longer-retention bisphosphonates blunt harder. (Oxford Academic) Romosozumab after denosumab drops from ~14–18% spine to ~5–8%, with total hip going to roughly zero. (nih) Anabolic-then-antiresorptive gives maximal BMD gain and possibly earlier fracture reduction versus the reverse order. (nih) And anabolic gains evaporate if you don’t follow with an antiresorptive. So if someone reflexively starts you on alendronate and you’d later want an anabolic, you’ve quietly spent something. Worth raising before anything gets prescribed.

#92

Have resisted the anabolics for some time, but now, six years after stopping the estradiol patch/prometrium, the DEXA score has virtually plummeted with negative 4.0 at the hip. So, time to reconsider . . ,

My endocrinologist was set to prescribe teraparatide, and I was in agreement. This is the med that my Medicare Advantage plan has in their formulary,

But then – I looked at my Promethease report, again, and saw that I have two genetic risks on two SNP’s that control the WNT16 pathway. What this does is cause the osteocytes to manufacture too much of a glycoprotein: sclerostin. This dampens down bone remodeling.

Once I understood that, I felt that Eventity, which works to reduce sclerostin, would be a better choice than teraparatide. So I quickly changed my insurance, and conveyed all the information to my endocrinologist with a request to prescribe Evenity rather than teraparatide. We’ll see if medicare approves (but with a negative 4.0, prior fractures, prior use of alendronates, they should).

The point of all this: it seems that doctors don’t have clear decision criteria for when to prescribe Evenity (romusuzumab) versus Forteo (teraparatide). But, if patients had genetic information (as well as oe markers) it would provide some individual evidence based information as a basis for choosing between these medications.

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