I used to work as a medical statistician before medical school … the incidence of the disease is critically important, a high incidence serious disease with an intervention that only makes a 10% rate reduction has a markedly bigger impact on all cause mortality than a low incidence less serious disease with an intervention that has a much bigger rate reduction. NNT is pretty important in any decision made to decide to treat. We also need to look at what outcome we are avoiding in the NNT and how this balances with the number of people needing to take the drug who don’t end up with benefit, but end up with risk/cost/side effects.
The extent of costs, side effects, alternatives must be factored before looking at whether Rx.
Naturally picking patients at high incidence of the given adverse outcome is important, and one’s ability to correctly pick those patients so that we treat patients at highest risk (which unfortunately we don’t do that great of a job predicting who will get spinal or hip fractures).
Irrespective, the decision to prescribe lipid medication is a more simple one than this - and I have very few patients who would meet any criteria to consider giving these medications.
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Come on, this is just nit-picking. Neither the results of the RCT or the OS trials were statistically significant, per the diagrams you just noted. His statement “taking these drugs has not been convincingly shown to prevent fracturing your hip in the first place” remains true, per the data presented.
Wait, now you’re expecting him to selectively dismiss the RR for the summation of the RCT+OS studies and just present the RR for the RCTs alone because that suits your pro-pharmacy narrative marginally better? And HE is the one who is biased?
“The RCTs were strictly designed, conducted, and
reported, and the OSs employed multivariate statistical
analysis to minimize potential confounding. The quality of
all included studies was regarded as high.”
Is your strategy here to just get so far into the weeds that nobody will actually get in there to check your work? Actually reading through the review paper (which took some doing to find the full text), re-listening to Dr. Greger’s video, and taking into account Dr. Fraser’s comments above, I think Greger has it right.
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AnUser
#64
Because a RCT is a better study design and doesn’t have confounding to a similar extent, so it is better able to detect causality.
Greger is wrong and knowingly so on so many topics, so it’s likely he is wrong on this one too.
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Sure, but there’s also the “totality of evidence”. Even if RCTs (if done well) are weighted more heavily than observational trials, it doesn’t mean one has to completely throw out the results of well-done observational trials, especially when both showed significant results in secondary prevention of hip fractures.
We’ll have to agree to disagree, then. Nobody’s perfect, but I think he’s right on the vast, vast majority of topics. And the statement “knowingly” implies that you have psychic powers.
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I love that you are on the board! You challenge me to think and evaluate what I do and recommend. Your points are well made. I’ll continue to refine my approach.
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Novel formulations of oral bisphosphonates in the treatment of osteoporosis
“The cardiovascular effects of bisphosphonates are debated, with data from animal studies (using higher dosages than used in human studies) suggesting potential cardiovascular protective effects due to reduced atherosclerosis in response to bisphosphonate therapy [27–30]. This is supported by a limited signal from a trial of risedronate which showed a protective effect of 2.5 mg dose for cardiovascular mortality (RR 0.69, 95% CI 0.49–0.99) and stroke mortality (RR 0.36, 95% CI 0.17–0.78), though this effect is caveated by the fact that there was no significant effect at the 5 mg dose or on the incidence of coronary artery disease [31]. Indeed, meta-analyses have shown no significant associations (either protective or adverse) between bisphosphonates and cardiovascular death, adverse cardiovascular outcomes, myocardial infarction or stroke [32] and this is echoed by long term, prospective database studies [33].”
“Oral bisphosphonates play a key role in the treatment of osteoporosis and the amelioration of fracture risk. They are, however, hampered by adverse events, particularly affecting the upper gastro-intestinal tract, which reduce patient adherence and persistence. Effervescent alendronate and gastro-resistant risedronate seek to improve adherence by simplifying the complex dosing rigmarole and reducing upper gastro-intestinal adverse events. Data from trials and real-world data are encouraging with regard to the benefits of these medications both clinically and from a health economic perspective.”
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Bisphosphonate drug holiday: who, when and how long
“The four nitrogen-containing bisphosphonates currently in clinical use for the treatment of osteoporosis differ in the strength for binding to bone. The rank order for binding affinity is zoledronate > alendronate > ibandronate > risedronate [Russell et al. 2008]. Higher-affinity bisphosphonates will bind avidly to the bone surface but will spread through bone more slowly, while lower-affinity agents will be distributed more widely through the bone but have a shorter residence time in bone if treatment is stopped. These agents also differ in the potency for inhibiting farnesyl pyrophosphate synthase. The rank order of potency for inhibiting this enzyme is zoledronate > risedronate >> ibandronate > alendronate [Russell et al. 2008]. Bisphosphonate use results in a rapid and substantial decrease in bone turnover markers that is dose and compound dependent, with a maximum effect in 3–6 months. This effect is maintained in a new steady state for at least 10 years with continued treatment [Bone *et al.*2004].“
“In conclusion, bisphosphonates that have been approved for the treatment of postmenopausal osteoporosis are effective and generally safe agents that have robust evidence for fracture risk reduction. Their systemic safety is related to their binding to bone and lack of uptake by other tissues other than the kidney. A reservoir of bisphosphonates accumulates after years of treatment that is gradually released over months or years and appears to result in a lingering antifracture benefit for some time after therapy is stopped.“
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[!]Chinese paper[!].
Non-nitrogen-containing bisphosphonates and nitrogen-containing bisphosphonates for the treatment of atherosclerosis and vascular calcification: A meta-analysis
“The role of non-nitrogen-containing bisphosphonates (non-N-BPs) and nitrogen-containing bisphosphonates (N-BPs) in the treatment of atherosclerosis (AS) and vascular calcification (VC) is uncertain. This meta-analysis was conducted to evaluate the efficacy of non-N-BPs and N-BPs in the treatment of AS and VC.”
“Non-N-BPs and N-BPs did not affect serum calcium, phosphorus or PTH levels. Non-N-BPs decreased serum TC levels and increased serum TG levels. N-BPs did not affect serum lipid levels. Non-N-BPs had a beneficial effect on VC, and N-BPs had a beneficial effect on AS.”
Cardiovascular Safety and Effectiveness of Bisphosphonates: From Intervention Trials to Real-Life Data
“Osteoporotic FF are known to increase mortality, thereby reducing the risk of new clinical fractures by means of antiosteoporosis drugs could also lead to a lowering in number of deaths. Currently, it is unclear whether this effect is a consequence of abatement of new fractures’ number or a direct result of pharmacological intervention with BSPs.”
“Despite these real-life results, a recent meta-analysis by Cummings and colleagues, including 27 clinical trials and 56,737 participants, concluded that no significant association subsists between BSPs and overall mortality, suggesting that BSPs cannot be recommended to increase life-span but only to reduce fracture risk [41].
In conclusion, even if some previous studies have reported that BSPs are associated with reduced mortality in addition to reduced fracture risk, currently there are no sufficient data to recommend the treatment for this reason alone, regardless of the personal risk of fracture. Conversely, it can be stated that mortality rates are no higher in BSP users, reassuring healthcare providers on their use in clinical practice to reduce fracture risk.“
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Rats.
Omega-3 attenuates the severity of medication-related osteonecrosis of the jaws in rats treated with zoledronate
Bisphosphonates enhance bacterial adhesion and biofilm formation on bone hydroxyapatite
“Adherence in the presence of pamidronate was higher than with other bisphosphonates. Density Functional Theory analysis showed that the protonated amine group of pamidronate, which are not present in clodronate or zoledronate, forms two additional hydrogen bonds with hydroxyapatite. Moreover, the reactive cationic amino group of pamidronate may attract bacteria by direct electrostatic interaction.”
“Conclusion: Increased bacterial adhesion and biofilm formation can promote osteomyelitis, cause failure of dental implants or bisphosphonate-coated joint prostheses, and complicate bone surgery in patients on bisphosphonates.”
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Short-term bisphosphonate treatment reduces serum 25(OH) vitamin D3 and alters values of parathyroid hormone, pentosidine, and bone metabolic markers
“This study demonstrated that serum 25(OH)D3 became significantly decreased after only 4 months of BP treatment in Japanese osteoporotic patients and confirmed that MIN more strongly inhibited bone turnover as compared with RIS.”
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