Mark W Lundy - Academia.edu (original) (raw)

Papers by Mark W Lundy

Research paper thumbnail of Reply to: A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

Research paper thumbnail of Skeletal Retention and Urinary Excretion of Nitrogen-Containing Bisphosphonates Including Fluorescently-labeled Bisphosphonates in Rats

Journal of Bone and Mineral Research, 2014

Research paper thumbnail of Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of New lower bone affinity bisphosphonate drug design for effective use in diseases characterized by abnormal bone resorption

Research paper thumbnail of A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

JBMR plus, Mar 3, 2021

ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about b... more ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Research paper thumbnail of Developments in the synthesis of new functionalized bisphosphonate drug candidates such as cyclic prodrugs

Phosphorus Sulfur and Silicon and The Related Elements, Jul 26, 2016

GRAPHICAL ABSTRACT ABSTRACT A new series of bisphosphonic acids bearing nitrogen containing heter... more GRAPHICAL ABSTRACT ABSTRACT A new series of bisphosphonic acids bearing nitrogen containing heterocycles and carbocycles has been designed and synthesized. The most potent novel bisphosphonates were shown to have lower mineral affinity but have better inhibition of farnesyl diphosphate synthase, than most clinically used bisphosphonates. However, the high polarity and charged nature of bisphosphonates result in very low oral bioavailability, resulting in highly variable absorption, especially when administered with food. To eliminate side effects and absorption issues while maintaining the bisphosphonate pharmacological activity, a series of novel potential prodrugs-cyclic esters of bisphosphonic acids was developed where the bisphosphonic acid functionality is “masked” as a cyclic ester. A new synthesis and the steric and structural isomerism of these novel cyclic bisphosphonates are discussed. The cyclic esters of bisphosphonates demonstrated better absorption, particularly in the presence of food when dosed orally. Also, several protected bisphosphonates were hydrolytically labile in vivo, thereby releasing the tetra-acid functionality of the bisphosphonates systemically after their oral absorption.

Research paper thumbnail of Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Fluorescently labeled risedronate and related analocs: Design and evaluation as imaging probes

Calcified Tissue International, 2008

We report synthesis of the first fluorescently labeled conjugates of risedronate (1), using an ep... more We report synthesis of the first fluorescently labeled conjugates of risedronate (1), using an epoxide linker strategy enabling conjugation of 1 via its pyridyl nitrogen with the label (carboxyfluorescein). Unlike prior approaches to create fluorescent bisphosphonate probes, the new linking chemistry did not abolish the ability to inhibit protein prenylation in vitro, while significantly retaining hydroxyapatite affinity. The utility of a fluorescent 1 conjugate in visualizing osteoclast resorption in vitro was demonstrated.

Research paper thumbnail of Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic St... more Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Ther... more Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Str... more Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic St... more Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic St... more Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of The Successful Design Of A Novel Highly Potent Nitrogen-Containing Bisphosphonate With Lower Bone Affinity

Research paper thumbnail of Bisphosphonate affinity to hydroxyapatite and farnesyl pyrophosphate inhibitory potency, together, drive in vivo efficacy

Journal of Bone and Mineral Research, 2007

Research paper thumbnail of Reply to: A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

JBMR Plus, 2021

To The Editor We thank Dr Pazianas for his comments emphasizing certain points raised in the disc... more To The Editor We thank Dr Pazianas for his comments emphasizing certain points raised in the discussion and conclusion of our article. There, we had endeavored to point out that this was a proofof-concept study testing the utility of a rapidly reversible bisphosphonate (NE-58025) in preventing bone loss. The only specific subsequent use for NE-58025 that we endorsed at this very early stage of research was to explore the biomechanical consequences of a drug holiday. This obviously points to a preclinical research study in which such bone biomechanical studies can be performed. We further noted that short-acting bisphosphonates that might require daily treatment could be problematic from a clinical perspective. We regret any confusion that might have resulted from our discussion. The letter also offers several speculations about negative “offtarget” (i.e., outside of bone) effects caused by high circulating levels of low-affinity bisphosphonate compounds, including the potential to d...

Research paper thumbnail of A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

JBMR Plus, 2021

ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about b... more ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adul...

Research paper thumbnail of Reply to: A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

Research paper thumbnail of Skeletal Retention and Urinary Excretion of Nitrogen-Containing Bisphosphonates Including Fluorescently-labeled Bisphosphonates in Rats

Journal of Bone and Mineral Research, 2014

Research paper thumbnail of Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of New lower bone affinity bisphosphonate drug design for effective use in diseases characterized by abnormal bone resorption

Research paper thumbnail of A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

JBMR plus, Mar 3, 2021

ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about b... more ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Research paper thumbnail of Developments in the synthesis of new functionalized bisphosphonate drug candidates such as cyclic prodrugs

Phosphorus Sulfur and Silicon and The Related Elements, Jul 26, 2016

GRAPHICAL ABSTRACT ABSTRACT A new series of bisphosphonic acids bearing nitrogen containing heter... more GRAPHICAL ABSTRACT ABSTRACT A new series of bisphosphonic acids bearing nitrogen containing heterocycles and carbocycles has been designed and synthesized. The most potent novel bisphosphonates were shown to have lower mineral affinity but have better inhibition of farnesyl diphosphate synthase, than most clinically used bisphosphonates. However, the high polarity and charged nature of bisphosphonates result in very low oral bioavailability, resulting in highly variable absorption, especially when administered with food. To eliminate side effects and absorption issues while maintaining the bisphosphonate pharmacological activity, a series of novel potential prodrugs-cyclic esters of bisphosphonic acids was developed where the bisphosphonic acid functionality is “masked” as a cyclic ester. A new synthesis and the steric and structural isomerism of these novel cyclic bisphosphonates are discussed. The cyclic esters of bisphosphonates demonstrated better absorption, particularly in the presence of food when dosed orally. Also, several protected bisphosphonates were hydrolytically labile in vivo, thereby releasing the tetra-acid functionality of the bisphosphonates systemically after their oral absorption.

Research paper thumbnail of Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition <i>In vivo</i&gt

Research paper thumbnail of Fluorescently labeled risedronate and related analocs: Design and evaluation as imaging probes

Calcified Tissue International, 2008

We report synthesis of the first fluorescently labeled conjugates of risedronate (1), using an ep... more We report synthesis of the first fluorescently labeled conjugates of risedronate (1), using an epoxide linker strategy enabling conjugation of 1 via its pyridyl nitrogen with the label (carboxyfluorescein). Unlike prior approaches to create fluorescent bisphosphonate probes, the new linking chemistry did not abolish the ability to inhibit protein prenylation in vitro, while significantly retaining hydroxyapatite affinity. The utility of a fluorescent 1 conjugate in visualizing osteoclast resorption in vitro was demonstrated.

Research paper thumbnail of Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic St... more Supplementary Figure 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Ther... more Supplementary Figure Legends 1-3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Str... more Supplementary Table 1 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic St... more Supplementary Figure 2 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic St... more Supplementary Figure 3 from Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth Inhibition In vivo

Research paper thumbnail of The Successful Design Of A Novel Highly Potent Nitrogen-Containing Bisphosphonate With Lower Bone Affinity

Research paper thumbnail of Bisphosphonate affinity to hydroxyapatite and farnesyl pyrophosphate inhibitory potency, together, drive in vivo efficacy

Journal of Bone and Mineral Research, 2007

Research paper thumbnail of Reply to: A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

JBMR Plus, 2021

To The Editor We thank Dr Pazianas for his comments emphasizing certain points raised in the disc... more To The Editor We thank Dr Pazianas for his comments emphasizing certain points raised in the discussion and conclusion of our article. There, we had endeavored to point out that this was a proofof-concept study testing the utility of a rapidly reversible bisphosphonate (NE-58025) in preventing bone loss. The only specific subsequent use for NE-58025 that we endorsed at this very early stage of research was to explore the biomechanical consequences of a drug holiday. This obviously points to a preclinical research study in which such bone biomechanical studies can be performed. We further noted that short-acting bisphosphonates that might require daily treatment could be problematic from a clinical perspective. We regret any confusion that might have resulted from our discussion. The letter also offers several speculations about negative “offtarget” (i.e., outside of bone) effects caused by high circulating levels of low-affinity bisphosphonate compounds, including the potential to d...

Research paper thumbnail of A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation

JBMR Plus, 2021

ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about b... more ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adul...